4-Pyridyl-and 2,4-pyrimidinyl-substituted pyrrole derivatives and their use in pharmacy

ABSTRACT

The present invention relates to 4-pyridyl- und 2,4-pyrimidinyl-substituted pyrrole derivatives and their use in pharmacy, of the formula 1  
                 
 
     in which the variables have the meanings indicated in the description.  
     The compounds according to the invention have immunomodulating and/or cytokine release-inhibiting action and are therefore utilizable for the treatment of disorders which are connected with a disturbance of the immune system.

[0001] The present invention relates to 4-pyridyl- and2,4-pyrimidinyl-substituted pyrrole derivatives having immunomodulatingand cytokine release-inhibiting action, pharmaceutical compositionswhich contain these compounds, and their use in pharmacy.

[0002] Pharmacologically active pyrrolizine compounds which inhibit5-lipoxygenase (5-LO) and cyclooxygenase-1 and -2 (Cox-1 and Cox-2) arealready known.

[0003] For example, pyrrolizine compounds having anti-inflammatoryactivity are described in Arch. Pharm. 319, 231-234 (1986), 318, 661-663(1985), 318, 663-664 (1985), 319, 500-505 (1986), 319, 749-755 (1986),327, 509-514 (1994), 330, 307-312 (1997), and in J. Med. Chem. 1987, 30,820-823 and 1994, 37, 1894-1897. The most promising compound of thistype is the 6-(4-chloro-phenyl)-7-phenyl-2,3-dihydropyrrolo [1,2-a]pyrrole compound ML 3000, see Drugs of the Future, 1995, 20, (10).:1007-1009. It suppresses the release of leukotrienes, thromboxanes andprostaglandins. The inhibitory action on the formation of theleukotrienes and the prostaglandins is balanced in this structure,harmful effects of a pure inhibitory action on cyclooxygenase -1 and -2(Cox-1 or Cox-2) with increased formation of leukotrienes are notobserved here. In all these compounds, the 1-position of the pyrrolizinestructure is unsubstituted.

[0004] WO 95/32970, WO 95/32971 and WO 95/32972 relate to compounds ofthe formula,

[0005] where

[0006] one or two of the radicals R¹, R² and R³ can be a mono- orbicyclic, aromatic, heterocyclic radical which has at least one oxygen,sulfur and/or nitrogen atom. These compounds have anti-inflammatoryaction.

[0007] Further fused pyrrole compounds and structurally similarcompounds pounds are described in U.S. Pat. Nos. 5,260,451, 4,546,100and 4,584,297; 4,684,658; 5,631,122; 3,920,672; 4,536,512; 5,552,422;4,539,400; 4,719,218; EP 608 133 A, DE 198 45 446 A, PCT/EP 99/09057 andDE 100 01 166. It is not disclosed that these compounds haveimmunomodulating or cytokine release-inhibiting action.

[0008] Surprisingly, it has now been found that certain fused pyrrolecompounds which have a 4-pyridyl substituent on the pyrrole ring haveimmunomodulating and/or cytokine release-inhibiting action.

[0009] The present invention therefore relates to the 4-pyridyl- and2,4-pyrimidinyl-substituted pyrrole derivatives and their use inpharmacy, of the formula I

[0010] in which

[0011] one of the radicals R¹, R² and R³ is a group of the formula

[0012] which is optionally substituted by one or two C₁-C₄-alkyl groupsor halogen atoms,

[0013] the second of the radicals R¹, R² and R³ is phenyl or thienyl,which is optionally substituted by one or two halogen atoms, and

[0014] the third of the radicals R¹, R² and R³ is H, CO₂H,CO₂C₁-C₆-alkyl, CH₂OH or C₁-C₆-alkyl,

[0015] R⁴ and R⁵ independently of one another are H or C₁-C₆-alkyl,

[0016] X is CH₂, S or O and

[0017] n is 1 or 2,

[0018] and the optical isomers, physiologically tolerable salts andphysiologically easily hydrolyzable esters thereof.

[0019] In the present case, the physiologically tolerable salts can beacid addition salts or base addition salts. For acid addition saltsinorganic acids are used, such as hydrochloric acid, sulfuric acid orphosphoric acid, or organic acids, such as tartaric acid, citric acid,maleic acid, fumaric acid, malic acid, mandelic acid, ascorbic acid,gluconic acid and the like.

[0020] Base addition salts include salts of the compounds of the formulaI with inorganic bases, such as sodium or potassium hydroxide, or withorganic bases, such as mono-, di- or triethanolamine.

[0021] Physiologically easily hydrolyzable esters of the compounds ofthe formula I are, for example, alkyl, pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl esters.

[0022] If the compounds according to the invention have asymmetriccenters, racemates and optical isomers (enantiomers, diastereomers) areincluded.

[0023] The expression “C₁-C₆-alkyl” includes straight-chain or branchedalkyl groups, such as methyl, ethyl, n-propyl, i-propyl, n-, i- or t-butyl, sec-butyl, n-pentyl and n-hexyl.

[0024] The expression “halogen” includes a fluorine, chlorine, bromineor iodine atom and in particular a fluorine or chlorine atom.

[0025] If the second of the radicals R¹, R² and R³ is phenyl, this ispreferably substituted by a halogen atom, in particular a fluorine atom.Preferably, the halogen atom is situated in the 4-position.

[0026] If the second of the radicals R¹, R² and R³ is thienyl, this ispreferably bonded in the 2-position. If the 2-thienyl group issubstituted, it is preferably substituted with a halogen atom and inparticular in the 5-position.

[0027] The preparation of the compounds according to the invention iscarried out according to various processes, depending on the position ofthe aromatic radicals and depending on the nature of the heteroaromaticradicals R¹, R² and R³.

[0028] The [α]-heterocyclically fused pyrrole compounds, in which X═S,or O, are prepared analogously to the processes described in WO95/32970, WO 95/32971 and WO 95/32972.

[0029] Examples 23 and 24 describe how 5H-furan-2-one precursors arecondensed with the acetic acid salts of aminoalcohols to give1-hydroxyalkyl-2-pyrrolones, which afford the [α]-hetero-cyclicallyfused pyrrole compounds with suitable condensing agents (here P₂S₅ ormethanesulfonyl chloride) (scheme 1).

[0030] The synthesis of the pyrrolizines, indolizines and their 1-thiaanalogs, with preferred positioning of pyridine and pyrimidine radicalin position 5 or 6 (R³) and 6 or 7 (R²), is carried out in the manner ofa 1,3-dipolar cycloaddition from appropriate münchnone or sydnoneprecursor compounds and suitable dienophiles or dipolarophiles (scheme2).

[0031] In this case, a pyridine or pyrimidine radical can be introducedon the one hand via the münchnone/sydnone component, on the other handvia the dipolarophile component. The dipolarophiles used aredehydrocinnamic acid esters, 3-substituted acetylenecarboxylic acidesters, 2-halogen-substituted cinnamic acids or 2-haloacrylates andnitrostyrenes.

[0032] In the group consisting of the pyrrolizines, N-acyl derivativesof proline (pyrrolidine-2-carboxylic acid, cf. examples 1-9, 19, 20, 22)are employed for sydnone formation, in the group consisting of thethiazolo [2,1-b] pyrroles (cf. examples 10-14) the N-acyl derivatives of[1,3]-thiazolidine-2-carboxylic acid) are used and in the groupconsisting of the indolizines N-acyl derivatives of the homologouspiperidine-2-carboxylic acid (cf. examples 15-18) are used.

[0033] For example, the cycloaddition of ethyl2-bromo-3-(4-pyridyl)-propenoate to the in situ-generated münchnone ofN-(4-fluoro-benzoyl)proline to give the ester from example 1, of ethyl2-bromo-3-(4-fluorophenyl)propenoate to the münchnone ofN-(isonicotinoyl)proline to give the ethyl ester of thepyrrolizinecarboxylic acid of example 19 and the cycloaddition of anethyl 2-bromo-3-(4-fluorophenyl)propenoate to the intramolecularlycyclized 3-(4-fluorobenzoyl)-[1,3]-thiazol-idine-2-carboxylic acid leadsto the pyrrolizine compound from example 10.

[0034] By the use of 1-nitrostyrenes and N-aroylproline, 7-(or 1-)unsubstituted 5,6- (or 2,3-)diarylpyrrolizine compounds are obtaineddirectly.

[0035] The reaction of 1-fluoro-4-(2-nitrovinyl)benzene with1-pyridine-4-carbonylpyrrolidine-2-carboxylic acid(N-isonicotinoyl-proline) leads to the compound from example 22.

[0036] Pyridine and pyrimidine substituents can also be introducedsubsequently into the activated pyrrole positions of the pyrrolizinesand indolizines and their thia and oxa analogs (schemes 3 and 4). Thereaction of 6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine withthe reactive 1-ethoxycarbonyl-pyridinium chloride obtained from ethylchloroformate and pyridine affords the compound of example 21 (R¹═CH₃,R²=4-fluorophenyl).

[0037] In particular the 3-amino-2,4-pyrimidine substituent can besynthesized starting from the acyl derivatives of themonoaryl-substituted compounds via condensation with dimethylformamidedimethyl acetal and guanidine (scheme 5).

[0038] The 3-amino-2,4-pyrimidine substituent can be introducedaccording to this method into each reactive, unsubstituted position ofthe pyrrole ring of the pyrrolizidine and indolizidine system.

[0039] The compounds according to the invention show in vitro and invivo immunomodulating and cytokine release-inhibiting action. They arethus suitable for the treatment of disorders which are connected with adisturbance of the immune system. For example, they are utilizable forthe treatment of autoimmune diseases, cancer, multiple sclerosis,arthritis, inflammatory bowel disease, septic shock, adult respiratorydistress syndrome, and in transplantations.

[0040] The compounds according to the invention can be administeredeither as individual therapeutic active compounds or as mixtures withother therapeutic active compounds. They can be administered as such,but in general they are administered in the form of pharmaceuticalcompositions, i.e. as mixtures of the active compounds with suitablepharmaceutical carriers or diluents. The compounds or compositions canbe administered orally or parenterally, but preferably they are given inoral dosage forms.

[0041] The type of pharmaceutical composition and of pharmaceuticalcarrier or diluent depends on the desired type of administration. Oralcompositions can be present, for example, as tablets or capsules and cancontain customary excipients, such as binders (e.g. syrup, acacia,gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g.lactose, sugar, cornstarch, calcium phosphate, sorbitol or glycine),lubricants (e.g. magnesium stearate, talc, polyethylene glycol orsilica), disintegrants (e.g. starch) or wetting agents (e.g. sodiumlauryl sulfate). Oral liquid preparations can be present in the form ofaqueous or oily suspensions, solutions, emulsions, syrups, elixirs orsprays etc. or as dry powders for reconstitution with water or anothersuitable carrier. Liquid preparations of this type can contain customaryadditives, for example suspending agents, flavorings, diluents oremulsifiers. For parenteral administration, solutions or suspensionswith customary pharmaceutical carriers can be employed.

[0042] The compounds or compositions according to the invention can beadministered to a mammal (human or animal) in doses of approximately 0.5mg to approximately 100 mg per kg of body weight per day. They can beadministered in an individual dose or in a number of doses. The spectrumof action of the compounds was investigated with the aid of thefollowing test systems.

[0043] In Vitro Test Procedure Using Human Whole Blood

[0044] Human potassium-EDTA whole blood (at 400 μl) is preincubated withtest substance for 15 min. at 37° C. in a CO₂ incubator (5% CO₂; 95%moisture-saturated air). The samples are then stimulated for 4 hourswith 1 μg/ml of LPS (E. coli 026:B6) at 37° C. in a CO₂ incubator (5%CO₂; 95% moisture-saturated air). The reaction is ended by placing thesamples on ice, addition of DPBS buffer and subsequent centrifugation(1000×g; 15 min). The plasma supernatant is used for the quantificationof IL-1β and TNFα by means of ELISA.

[0045] In Vitro Test Procedure Using PBMCs

[0046] The mononuclear cells (PBMCs) are isolated from humanpotassium-EDTA whole blood diluted 1:3 by means of density gradientcentrifugation (Histopaque®—1.077). After 2 washing steps with DPBSbuffer, the mononuclear cells are resuspended in macrophage-SFM mediumand adjusted to a cell count of 1×10⁶ cells/ml.

[0047] The PBMCs suspension (at 390 μl) is preincubated with testsubstance for 15 min at 37° C. in a CO₂ incubator (5% CO₂; 95%moisture-saturated air). The samples are subsequently stimulated for 4hours with 1 μg/ml LPS (E.coli 026:B6) at 37° C. in a CO₂ incubator (5%CO₂, 95% moisture-saturated air). The reaction is ended by placing thesamples on ice, addition of DPBS buffer and centrifugation (15880×g; 12min). The supernatant is used for the quantification of IL-1β and TNFαby means of ELISA.

[0048] In Vitro Test System for Determining the Inhibition of5-Lipoxygenase

[0049] Human granulocytes are used as a source of the 5-lipoxygenase.LTB4 (leukotriene B4) is formed from endogenous arachidonic acid bymeans of stimulation with calcium ionophore A 23187. The granulocytesare isolated and the enzyme reaction is carried out according to knownprocesses (see Arch. Pharm. Pharm. Med. Chem. 330, 307-312 (1997)).

[0050] The blood, which is protected from clotting with heparin, iscentrifuged on a discontinuous Percoll® gradient and the granulocytelayer is pipetted off. After lysis of the erythrocytes, the granulocytesare washed a number of times and then adjusted to a specific cell count.The enzyme reaction is then started with calcium ionophore A 23187 inthe presence or absence of the test substance after addition of Ca2+.The synthesis of the leukotrienes is stopped after 1.5 minutes. Thesamples are centrifuged off and the supernatant is diluted. LTB4 isdetermined quantitatively by means of ELISA.

[0051] In Vitro Test System for Determining the Inhibition ofCyclooxygenase-1

[0052] In this test system, the amount of prostaglandin E2 formed fromhuman platelets after addition of calcium ionophore is determined bymeans of ELISA. In this process, the platelets are obtained aftercentrifugation on a discontinuous Percoll® gradient. The enzyme reactionand the determination of the metabolites formed is carried out inprinciple as in the determination of 5-lipoxygenase inhibition.Differences exist with respect to the incubation time. Furthermore, theaddition of a thromboxane synthesis inhibitor is necessary (see Arch.Pharm. Pharm. Med. Chem. 330, 307-312 (1997)).

[0053] In Vitro Test System for Determining the Inhibition ofCyclooxygenase-2

[0054] COX2 (from sheep placenta) is preincubated at 4° C. with testsubstance for 10 min, then stimulated with arachidonic acid (5 μM) at25° C. for 10 min. Diclofenac is used as a reference (IC50(COX2)=3.010⁻⁶ M). The determination is carried out at 3 dilutions (10⁻⁷, 10⁻⁶,10⁻⁵ M). The PGE2 concentrations are quantified by means of ELISA (seeMitchell J. A. et al., Proc. Nat. Acad. Sci. 90: 11693-11697 (1993)).TABLE 1 Influence of the test compounds on the release of inflammatorymediators (IC₅₀ values in μmol, and percentage inhibition in μmol[μmol/%]): Example Structure COX-1 COX-2 5-LO TNFα IL-1β 1A

— — — PBMC: 10/13 whole-blood method: 30 PBMC: 10/21 whole-blood method:30 2

— — — PBMC: 10/37 whole-blood method: 16 PBMC: 10/17 whole-blood method:2.9 3

— 5.7 3.7 PBMC: 4.0 whole-blood method: 28 PBMC: 5.0 whole-blood method:22 4

 1.9 3.4 2.4 PBMC: 6.0 whole-blood method: 41 PBMC: 5.7 whole-bloodmethod: 59 5

— 5.8 0.027 PBMC: 1.4 10/88 1/44 PBMC:  10/− 1B

— n.d. 2.0 PBMC: 1.4 10/60 1/12 PBMC: 1.4 10/−1/+ 7

10/40 whole-blood method: 48 whole-blood method: 52 9A

10/11 1.3 PBMC: 10/38 whole-blood method: 38 PBMC: 10/47 whole-bloodmethod: 22 10A

 3.4 6.1 0.065 PBMC: 10.0 whole-blood method: 30 PBMC: >100.0whole-blood method: 30 11

10/33 — 10/30 PBMC: 6.8 whole-blood method: 100/45 PBMC: 2.3 whole-bloodmethod: 100/45 12

PBMC: 10/44 whole-blood method: 45 PBMC: 7.6 whole-blood method: 76 13

10/45 0.04 PBMC: 8.1 whole-blood method: 41 PBMC: 10/43 whole-bloodmethod: 80 14

 2.3 2.4 PBMC: 7.6 whole-blood method: — PBMC: 8.5 17

10/48 2.2 PBMC: 4.0 whole-blood method: 39 PBMC: 10.0/67 1.0/0.0whole-blood method: 33 18

10/35 1.6 3.3 PBMC: 10.0/65 1.0/33 0.1/16 whole-blood method: 37 PBMC:7.5 whole-blood method: 36 19A

 2.9 5.5 2.05 PBMC: 10.0/60 1.0/0 PBMC: 10.0/21 1.0/0 21

0.13 PBMC: 0.34 whole-blood method: 6.0 10/33 — PBMC: 26 PBMC: 5.6whole-blood method: 37 22

0.23 1.5 0.67 PBMC: 10/34 PBMC: 10/59 1/+ 23

10/83 1.0/0  3.5 PBMC: 10/50 1/10 4.0 0.05 PBMC: 10/79 1/0 PBMC: 1/19 24

4.0 1.35 PBMC: 10/42 PBMC: 10/48 25

— — — PBMC: 87 PBMC: 100/+++

EXAMPLE 1A Ethyl3-(4-fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0055] a) N-(4-Fluorobenzoyl)proline

[0056] L-Proline (15.0 g, 130 mmol) is dissolved in NaOH (5%, 150 ml,190 mmol) and the solution is cooled in an ice bath (0-5° C.).4-Fluorobenzoyl chloride (19.0 g, 120 mmol) is added dropwise withvigorous stirring, the cooling is removed and stirring is continued for1 h. After acidifying the reaction mixture with HCl (10% strength, 45ml) the amide deposits in large lumps, which are comminuted, suspendedusing water, filtered off with suction and washed with water (50 ml).The substance is dried over P₂O₅ in vacuo: 24.41 g.

[0057] M.p.: 174.0° C., yield: 79%; C₁₂H₁₂FNO₃; MW=237.23.

[0058] IR (KBr): 1/λ (cm⁻¹)=1735, 1605, 1585, 1514, 1440, 1230, 1180,1161, 856, 762 513;

[0059]¹H-NMR (CDCl₃:) δ[ppm]=7.64−7.57 (m, 2H,); 7.16−7.07 (m, 2H);4.78−4.71 (m, CH); 3.63−3.57(CH₂); 2.36−1.85 (m; 2 CH₂).

[0060] b) Bromocarbethoxymethylenetriphenylphosphorane

[0061] Carboethoxymethyltriphenylphosphonium bromide (43 g, 100 mmol) isdissolved in water (100 ml) and cooled in an ice bath. NaOH (10%, 40 ml,100 mmol) is added dropwise at 0-5° C. until a pH of 9 is reached. Thedeposited resinous mass is separated off, digested with ether and thecrystals formed are filtered off with suction (31 g, 87%). The substanceis dried over CaCl₂ in a desiccator in the dark.

[0062] The dried compound (carboethoxymethylidenetriphenyl-phosphorane,30 g, 0.086 mol) is dissolved in CH₂Cl₂ (160 ml) and the solution iscooled to 5° C. in an ice bath. A solution of bromine (13.9 g, 0.087mol) in CH₂Cl₂ (40 ml) is slowly added dropwise and the batch is stirredfor a further 30 min until the disappearance of the bromine coloration.

[0063] The organic phase is washed first with water (50 ml), then twicewith NaHCO₃ solution (100 ml) in a separating funnel until all of theHBr is neutralized. The CH₂Cl₂ phase is dried over Na₂SO₄ sicc. andconcentrated in vacuo. The residue is crystallized from acetone/n-hexane(60 ml, 2:1). The crystals are washed with this mixture (40 ml) anddried in vacuo: 27.5 g.

[0064] M.p.: 151.9° C., yield: 75%; C₂₂H₂₀BrO₂P; MW=427.28.

[0065] IR (KBr): 1/λ (cm⁻¹)=2981, 1650, 1583, 1434, 1301, 1101, 693;

[0066]¹H-NMR (CDCl₃:) δ[ppm]=7.73−7.44 (m; 15H, ar.); 3.935 (q; J=7 Hz,2H); 0.885 (t; J=7 Hz, CH₃).

[0067]¹³C-NMR (CDCl₃:) δ[ppm]=162.5, 149.8, 141.8, 137.9, 123.7, 118.1,63.2, 14.1.

[0068] c) Ethyl 2-bromo-3-(4-pyridyl)propenoate

[0069] Bromocarbethoxymethylenetriphenylphosporane (9.0 g, 21 mmol) isdissolved in toluene (60 ml) with the exclusion of light and then asolution of isonicotinaldehyde (4-pyridinecarbaldehyde, 2.14 g, 20 mmol)in toluene (9 ml) is added. The batch is stirred in the dark at RT for16 h. The solution is then concentrated in vacuo, the residue isdigested with ether (40 ml) and the ether phase is filtered off withsuction from the crystalline solid. The crystals are washed a further 2times with ether (10 ml) and the collected ether solutions areconcentrated in vacuo. The residue which remains (6.63 g) is purified bycolumn chromatography (cc) on Al₂O₃ using an ether/n-hexane mixture(2:1). The substance sought appears in the fractions 1-5: 4.9 g of darkbrown oil.

[0070] Yield: 95.7%; C₁₀H₁₀BrNO₂; MW=256.10.;

[0071]¹H-NMR (CDCl₃:) δ[ppm]: 8.72−8.69/7.66−7.63 (AA′BB′; 4H, ar.);8.12 (s, 1H); 4.43−4.32 (q, J=7.1 Hz, 2H, CH₂); 1.44−1.37 (t; J=7.1 Hz,CH₃)

[0072]¹³C-NMR (CDCl₃:) δ[ppm]: 162.5,; 149.8,; 141.8,; 137.9,; 123.7,;118.1,; 63.2,; 14.1

[0073] d) Ethyl3-(4-fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0074] N-(4-Fluorobenzoyl)proline (9.48 g, 40 mmol) is suspended inacetic anhydride (60 ml), raised to a temperature of 80° C. in a refluxapparatus under argon until a clear solution is obtained (20 min), thentreated dropwise with ethyl 2-bromo-3-(4-pyridyl)acrylate (12.28 g, 8mmol) in toluene (10 ml) (8 min) and the reaction vessel is immersed ina prepared hot oil bath (120° C.). The dark mixture is heated underreflux for 21 h, whereupon starting material is no longer detectable bytlc (Al₂O₃; ethyl acetate/n-hexane 1:1). The reaction solution is cooledand treated with ethyl acetate (50 ml), and the organic supernatant ispoured off. The solid deposited in the flask is digested 2 times withethyl acetate (30 ml) in the presence of heat. Supernatant and ethylacetate solutions are combined and concentrated in vacuo. The residue istaken up in ethyl acetate (200 ml) and the ethyl acetate phase is washeduntil neutral with water (100 ml), NaHCO₃ solution (100 ml) and wateragain (100 ml), dried (Na₂SO₄ sicc.) and concentrated. A pale beigesolid crystallizes from the concentrated ethyl acetate phase (30 ml).After filtering off with suction, washing (ethyl acetate) and afterdrying, 2.93 g of the product sought remain.

[0075] After concentrating the mother liquor, a further 2.1 g of acrystallizate are obtained which is a mixture of product and by-product.

[0076] Yield: 21%, C₂₁H₁₉FN₂O₂; MW=350.40.

[0077] IR (KBr): 1/λ (cm⁻¹)=2985, 1695, 1510, 1222, 1136, 1093, 839,584, 525

[0078]¹H-NMR (CDCl₃:) δ[ppm]=8.46−8.43/7.14−7.11 (AA′BB′; 4H, —pyridyl);7.10−6.92 (m; 4H, ar.); 4.22−4.12 (q; J=7.1 Hz, 2H); 4.02−3.95 (t; J=7.2Hz, 2H); 3.27−3.19 (t; J=7.5 Hz, 2H); 2.63−2.48 (m; J=7.3 Hz, 2H);1.24−1.17 (t;J=7.2 Hz, CH₃)

[0079]¹³C-NMR (d₆-DMSO): δ[ppm]=164.5, 148.9, 145.2, 143.5, 131.1,131.0, 127.2, 156.0, 115.8, 115.4, 59.4, 46.8, 26.6, 26.4, 14.3.

EXAMPLE 1B Ethyl3-(4-fluorophenyl)-1-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-2-carboxylate

[0080] CC separation of the mixed crystallizate (2.1 g) obtained underexample 1A, d):

[0081] Separation on Al₂O₃— ether/THF 9:1: fractions 6-9: substance 1A(1.15 g)

[0082] Fraction 10-12: mixture of 1A+1B;

[0083] fractions 13-end: substance 1B (0.3 g);

[0084] yield: 0.3 g (2%) C₂₁H₁₉FN₂O₂; MW=350.40.

[0085] IR (KBr): 1/λ (cm⁻¹)=2983, 1702, 1600, 1523, 1489, 1435, 1218,1171, 1161, 1028, 849, 834,

[0086]¹H-NMR (CDCl₃) δ[ppm]=8.56−8.53/7.32−7.29 (m; 4H,—pyridyl);7.48−7.41/7.16−7.07 (m; 4H, ar.); 4.09−3.99 (q; J=7.1 Hz, 2H); 3.92−3.85(t; 7.1 Hz, CH₂); 3.03−2.95 (t; J=7.3 Hz, CH₂); 2.58−2.48 (quin; J=5.4Hz, CH₂); 1.02−0.94 (t; J=7.2 Hz, CH₃)

[0087]¹³C-NMR (CDCl₃): δ[ppm]=165.1; 163.8; 160.1; 149.2; 143.7; 136.7;133.0; 131.8; 131.6; 127.8; 123.8; 115.2; 114.8; 59.7; 46.1; 27.0; 24.5;13.7

EXAMPLE 23-(4-Fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylicacid

[0088] Ethyl3-(4-fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate(example 1A, 1.0 g, 2.8 mmol) is refluxed in an ethanolic KOH (10%, 10ml, 18 mmol) for 16 h. The ethanol is then evaporated in vacuo, and theresidue is taken up in water (10 ml) and neutralized using dil. HCluntil the free acid has completely deposited. This is filtered off withsuction, washed with water and dried in vacuo. 0.78 g is obtained.

[0089] M.p.: dec.; yield: 85%; C₁₉H₁₅FN₂O₂; MW=322.34.

[0090] IR (KBr): 1/λ (cm⁻¹)=1683, 1602, 1512, 1149;

[0091]¹H-NMR (CDCl₃/d₆-DMSO) δ[ppm]=8.40−8.37/7.19−7.16 (AA′BB′;4H,—pyridyl); 7.07−6.92 (m; 4H, ar.); 3.98 (t; J=7.1 Hz, CH₂); 3.23 (t;J=7.4 Hz, CH₂) 2.92 (s; OH); 2.54 (t; J=7.3 Hz, CH₃)

[0092]¹³C-NMR (CDCl₃/d₆-DMSO): δ[ppm]=165.8, 164.2, 159.3,; 148.4,;145.3,; 143.6, 131.2, 131.0, 127.4, 127.3, 126.5, 126.0, 123.8, 115.6,115.2, 105.9, 46.6, 26.5, 26.2.

EXAMPLE 3[3-(4-Fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizin-1-yl]methanol

[0093] Ethyl3-(4-fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate(example 1A, 4.56 g, 13 mmol) is dissolved in abs. THF (100 ml) underargon and Na bismethoxyethoxyaluminum hydride (Vitride^(R)) is addeddropwise through a septum via the cannula of a syringe (20 min). Themixture is stirred at 50° C. for 2 h, whereupon starting material is nolonger detectable by tlc (Al₂O₃— ethyl acetate/n-hexane 3:7), then it isallowed to cool. H₂O (25 ml) is cautiously added dropwise to thereaction solution, then it is concentrated in vacuo (THF evaporates),and the aqueous organic residue is treated with ethyl acetate (100 ml).The phases are separated. The organic phase is washed 2 times with water(40 ml), dried over Na₂SO₄ sicc. and concentrated in vacuo (5.0 g). Thereddish brown-colored, resinous residue is crystallized from diethylether (10 ml). The crystals are washed with ethyl acetate (5 ml) andether (5 ml) and dried.

[0094] 3.67 g of the compound sought remain

[0095] Yield: 91.5%; C₁₉H₁₇FN₂O; MW=308.35;

[0096]¹H-NMR (CDCl₃): δ[ppm]=8.43−8.40 and 7.21−7.18 (AA′BB′; 4H,—pyridyl); 7.18−7.12 (m; 2H, ar.); 7.05−6.95 (m; 2H, ar.); 4.55 (s;CH₂); 3.96 (t; J=7.0 Hz, CH₂); 3.01 (t; J=7.3 Hz, CH₂); 2.53 (quin;J=7.1 Hz, CH₂).

EXAMPLE 45-(4-Fluorophenyl)-7-methyl-6-(4-pyridyl)-2,3-dihydro-1H-pyrrolizine

[0097][3-(4-Fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizin-1-yl]methanol(3.08 g, 10 mmol) is heated with hydriodic acid (57%, 18 ml, 134 mmolHI) in an oil bath at 120° C. (reflux). The initially undissolvedsubstance has dispersed in the batch after 45 min, and starting material(rf=0.05) is no longer detectable (product rf=0.9, iodide rf=0.6) by tlc(ether, Al₂O₃). After cooling (1 h), the solution is diluted with 50 mlof water and covered with a layer of 100 ml of ethyl acetate. The waterphase is carefully neutralized with sat. Na₂CO₃ soln (30 ml) and thephases are separated. The water phase again extracted with ethyl acetate(50 ml), the combined ethyl acetate extracts decolorized using sodiumthiosulfate solution (Na₂S₂O₃, 2% strength, 40 ml) and, after washingagain with water (50 ml), dried over Na₂SO₄ sicc. After evaporating thesolvent in vacuo, 2.28 g of residue remain, which solidifies fromCH₂Cl₂/ethyl acetate to give a resinous mass. The substance is purifiedby CC (Al₂O₃/ether) and the substance obtained from the fractions byevaporating the solvent (fractions 1-17, 1.74 g) is crystallized fromdiisopropyl ether. 1.37 g of pure compound are obtained.

[0098] Yield: 47%; C₁₉H₁₇FN₂; MW=292.36

[0099]¹H-NMR (CDCl₃) δ[ppm]=8.45−8.41/7.07−7.03 (AA′BB′; 4H,—pyridyl);7.17−6.93 (m; 4H, ar.); 3.945 (t; J=6.9 Hz, CH₂); 2.88 (t; J=7.2 Hz,CH₂); 2.51 (quin; J=7.0 Hz, CH₂); 2.10 (s; CH₃)

[0100]¹³C-NMR (CDCl₃): δ[ppm]=164.2; 159.2; 149.5; 144.7; 135.5; 130.7;130.6; 128.6; 128.5; 124.9; 124.6; 122.8; 115.7; 115.3; 108.4; 46.1;27.2; 23.3; 10.5

EXAMPLE 5 5-(4-Fluorophenyl)-6-(4-pyridyl)-2,3-dihydro-1H-pyrrolizine

[0101] Ethyl3-(4-fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate(example 1A, 2.63 g, 7.5 mmol) is firstly dissolved at RT usinghydriodic acid (57%, 7.5 ml, 56 mmol HI). The hydroiodide which hascrystallized out again after a few minutes is brought into solutionagain by warming to 70° C. and the mixture is refluxed for 2 h. In thistime, after about 45 min and after 1 h, in each case 2 further portionsof HI (57%, a 3 ml, 45 mmol) are added. After passage of the reactiontime, starting material (rf=0.4) is no longer detectable by tlc (Al₂O₃,ether—THF 9:1). For the isolation of the product (rf=0.55), theprecipitate of the crystallized hydriodide product formed on cooling isfiltered off with suction, purified of adhering HI by washing with water(3 times 10 ml) and dried. 2.57 g of hydriodide (84.3%) are isolated.

[0102] Isolation of the Base:

[0103] 5-(4-Fluorophenyl)-6-(4-pyridyl)-2,3-dihydro-1H-pyrrolizinehydriodide (3.68 g, 9 mmol) is suspended in CH₂Cl₂ (150 ml) andintensively stirred with saturated NaHCO₃ solution (100 ml). The CH₂Cl₂phase is then separated off, dried using Na₂SO₄ sicc. and concentratedin vacuo. The residue is taken up in a little ether and the crystalsformed are filtered off with suction and dried: 2.39 g.

[0104] Yield: 80%, C₁₈H₁₅FN₂; MW=278.33

[0105] IR (KBr): 1/λ (cm⁻¹) =1594, 1525, 1508, 1426, 1356, 1216, 833,787;

[0106]¹H-NMR (CDCl₃) δ[ppm]=8.38−8.35/7.11−7.09 (AA′BB′; 4H,—pyridyl);7.31−7.24 (m; 2H, ar.); 7.11−7.02 (m; 2H, ar.); 6.15 (s; 1H); 3.89 (t;J=7.0 Hz, CH₂); 2.945 (t; J=7.2 Hz, CH₂); 2.51 (quin; J=7.0 Hz, CH₂);

[0107]¹³C-NMR (CDCl₃): δ[ppm]=160.0, 157.0, 149.2, 145.0, 137.7, 131.2,131.1, 128.8, 122.0, 116.1, 115.6, 99.8, 45.9, 27.4, 24.5

EXAMPLE 6A Ethyl3-(2-thienyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0108] a) N-(2-Thienylcarbonyl)proline

[0109] L-Proline (2.42 g, 21 mmol) is dissolved in NaOH (5%, 30 ml, 38mmol) and the solution is cooled in an ice bath (5° C.).Thiophene-2-carbonyl chloride (2.93 g, 20 mmol) is slowly added dropwisewith stirring (10-15 min), in the course of which the temperature shouldnot exceed 7° C. The mixture is stirred at 5-7° C. for 1 h, the coolingis removed and stirring is continued for 1 h at RT. After acidifying thereaction mixture with HCl (10% strength, 12 ml) the amide deposits inoily form. The oil is extracted with ethyl acetate (300 ml), the ethylacetate phase is washed a number of times with water (200 ml), dried(Na₂SO₄ sicc.) and the solvent is evaporated in vacuo. The residue (4.16g) is suspended twice using hot water (20 ml), filtered off with suctionand washed with diisopropyl ether (10 ml). The substance is dried overP₂O₅ in vacuo (tlc:

[0110] RP 18/MeOH, rf=0.75): 3.87 g.

[0111] M.p.: 143.0° C., yield: 81.6%; C₁₂H₁₂FNO₃; MW=237.23.

[0112] IR (KBr): 1/λ (cm⁻¹)=3091, 3078, 1717, 1601, 1524, 1439, 1406,1262, 1240, 1195, 773, 757, 736;

[0113]¹H-NMR (CDCl₃:) δ[ppm]=7.70 and 7.68 (d; J=3.7 Hz, 1H) 7.62 and7.59 (d; J=5.0 Hz,1H) 7.16−7.12 (dd; 1H) 4.85−4.79 (m; 1H) 3.94−3.87 (m;CH2) 2.50 (m;1H) 2.12 (m; 3H);

[0114] b) Ethyl3-(2-thienyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0115] N-(2-Thienylcarbonyl)proline (4.69 g, 21 mmol) is dissolved inacetic anhydride (15 ml) at 60° C. (15 min), ethyl2-bromo-3-(4-pyridyl)propenoate (6.40 g, 25 mmol) is added to the clearsolution and the mixture is heated at 90° C. for 16 h, whereupon a tlcsample (Al₂O₃-ethyl acetate/THF 9:1) no longer indicates startingmaterial. The cooled reaction mixture is treated with ethyl acetate (120ml) and intensively stirred with saturated Na₂CO₃ solution (80 ml) for15 min and diluted with water (50 ml). The ethyl acetate phase isseparated off, the water phase is extracted with a further 3 portions ofethyl acetate (150 ml), and these organic phases are combined, washedwith saturated Na₂CO₃ soln (50 ml) and, after drying (K₂CO₃ sicc.),concentrated in vacuo. 8 g are obtained as a residue, which is dissolvedin a little ethyl acetate and purified by cc (Al₂O₃-ethylacetate/n-hexane 2:1).

[0116] Fractions 6-12: contain the substance sought, which crystallizesfrom ether/diisopropyl ether, is filtered off with suction and dried:2.63 g.

[0117] Yield: 37%, C₁₉H₁₈N₂O₂S, MW=338.43;

[0118]¹H-NMR (CDCl₃:) δ[ppm]=8.52−8.49/7.23−7.20 (AA′BB′; 4H, —pyridyland 1H;—thiophene); 6.925 (dd; J=3.6 Hz, 1H); 6.75 (d; J=3.5 Hz, 1H);4.20−4.07 (m; 4H, CH₂); 3.23 (t; J=7.5 Hz, CH₂); 2.575 (quin; J=7.3 Hz,CH₂); 1.173 (t; J=7.1 Hz, CH₃)

[0119] Fractions 13-15: Mixed fraction with product from example 6B:0.23 g

EXAMPLE 6B Ethyl3-(2-thienyl)-1-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-2-carboxylate

[0120] From CC purification of example 6A (Al₂O₃-ethyl acetate/n-hexane2:1):

[0121] Fractions 19-30: contains the positional isomer compound, whichlikewise crystallizes in pure form from ether/diisopropyl ether, isfiltered off with suction and dried: 0.19 g.

[0122] Fractions 31-end: contains compound 6B contaminated withN-(2-thienylcarbonyl)proline.

[0123] Yield: 2.7%, C₁₉H₁₈N₂O₂S, MW=338.43;

[0124]¹H-NMR (CDCl₃:) δ[ppm]=8.56−8.53 (AA′BB′; 2H,—pyridyl); 7.43−7.40(d; J=3.1 Hz, 1H,—thiophene); 7.30−7.29 (m; 3H, —pyridyl and—thiophene);7.12−7.08 (dd; J=3.7 Hz, 1H); 4.15−3.99 (m; 4H, CH₂); 2.99 (t; J=7.3 Hz,CH₂); 2.53 (quin; J=7.2 Hz, CH₂); 1.035 (t; J=7.2 Hz, CH₃).

EXAMPLE 73-(2-Thienyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylic acid

[0125] Analogously to Example 2:

[0126] Ethyl3-(2-thienyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate(example 6A, 1.5 g, 4.4 mmol) is stirred in ethanolic KOH (8%, 15 ml, 21mmol) for 16 h at 60° C., the ethanol is evaporated in vacuo, and theresidue is suspended in water (40 ml) and brought to pH4 in an ice bathusing dil. H₃PO₄ (8%). The red-brown precipitate formed is filtered offwith suction, washed with water and dried in vacuo. 1.17 g are obtained.

[0127] M.p.: dec.; yield: 85%; C₁₉H₁₅FN₂O₂; MW=322.34.

[0128] IR (KBr): 1/λ (cm⁻¹)=1676, 1604, 1567, 1420, 1305. 1196, 1012,852, 702;

[0129]¹H-NMR (CDCl₃) δ[ppm]=8.49−8.46/7.53−7.50 (AA′BB′; 4H,—pyridyl);7.335 (d; J=3.1 Hz, 1H,—thiophene); 7.00 (d; J=3.7 Hz, 1H); 6.81 (dd,1H,—thiophene); 4.79 (s, OH) 4.07 (t; J=7.1 Hz, CH₂); 3.28 (t; J=7.3 Hz,CH₂); 2.585 (m; CH₂).

EXAMPLE 8 5-(2-Thienyl)-6-(4-pyridyl)-2,3-dihydro-1H-pyrrolizine

[0130]3-(2-Thienyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylic acid(example 7, 0.2 g, 0.64 mmol) is heated under argon in a 10 ml flask byimmersing in a metal bath at 250° C. Evolution of CO₂ takes placeimmediately, and the substance melts and turns black. After cooling, thesolidified, glassy melt is taken up in CH₂Cl₂ (10 ml) and filteredthrough Al₂O₃ (TSC, Baker). The filter cake is eluted with diethylether. The eluate is concentrated and crystallizes fromether/diisopropyl ether in the cold: white crystals 0.04 g.

[0131] Yield: 23%; C₁₆H₁₄N₂S; MW=266.37.

[0132]¹H-NMR (CDCl₃) δ[ppm]=8.44−8.41/7.27−7.24 (AA′BB′; 4H,—pyridyl);7.385 (dd, 1H,—thiophene); 7.07 (d; 2H,—thiophene); 6.99−6.97 (d;1H,—thiophene); 6.16 (s; 1H); 3.955 (t; J=7.1 Hz, CH₂); 2.94 (t; J=7.3Hz, CH₂); 2.52 (quin; J=7.2 Hz, CH₂)

EXAMPLE 9A Ethyl3-(5-chloro-2-thienyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0133] a) (5-Chloro-2-thienylcarbonyl chloride

[0134] 5-Chlorothiophene-2-carboxylic acid (4.0 g, 24.6 mmol) isdissolved in dichloroethane (10 ml) and thionyl chloride (SOCl₂, 2.7 ml,4.4 g, 37 mmol) is added, after inoculating with a drop of DMF the batchis heated to 50° C. (IT). The course of the reaction is monitored by tlc(SiO₂/ether: product rf 0.8, starting material rf 0.1-0.3). After 1.5 hand after 2.5 h, in each case SOCl₂ (5 drops) was added. After 4.5 h,the pale yellow solution is concentrated on a Rotavapor and the residueis fractionally distilled: at 50 mbar 4.0 g of product (89.9%) isobtained at the distillation temperature of 110° C.

[0135] Yield: 4.0 g ( 90%); C₅H₂Cl₂OS; MW=181.04.

[0136]¹H-NMR (CDCl₃:) δ[ppm]=7.80/7.05 (AB; 2H, J_((AB))=4 Hz)

[0137] b) N-(5-Chloro-2-thienylcarbonyl)proline

[0138] 5-Chlorothiophene-2-carbonyl chloride (3.62 g, 20 mmol) is slowlyadded dropwise with stirring (10-15 min) to a solution of L-proline(2.42 g, 21 mmol) in NaOH (5%, 32 ml, 40 mmol) cooled to 5° C. in an icebath, the temperature not exceeding 9° C. The mixture is stirred at 5-7°C. for 30 min, in the course of which a precipitate slowly forms whichis brought into solution again by addition of water (8 ml). The batch isstirred at RT for a further 90 min. After acidifying the reactionmixture with HCl (10% strength, 12 ml, pH 3.5), the amide deposits incrystalline form after stirring for 30 min. The crystals are filteredoff with suction, washed a number of times with water (200 ml) anddried: crystallizate 1=2.61 g.

[0139] The mother liquor is acidified to pH 1-2 using HCl and thevoluminous precipitate formed is likewise filtered off with suction andwashed until neutral with water and dried: crystallizate 2: 2.17 g.

[0140] Both crystallizates are the substance sought: total yield 4.78 g.

[0141] Yield: 92%; C₁₀H₁₀ClNO₃S; MW=259.71.

[0142]¹H-NMR (CDCl₃:) δ[ppm]=8.50 (s; OH) 7.43/6.94 (AB; 2H,—thiophene,J_((AB))=4 Hz); 4.77−4.72 (m; 1H); 3.91−3.77 (m; CH₂); 2.37−2.12 (m; 4H,CH₂)

[0143] c) Ethyl3-(5-chloro-2-thienyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0144] N-(5-Chloro-2-thienylcarbonyl)proline (1.1 g, 4.2 mmol) isdissolved in acetic anhydride (3 ml) at 50° C. (IT) (15 min), ethyl2-bromo-3-(4-pyridyl)propenoate (1.29 g, 5.0 mmol is added to the clearsolution and the mixture is heated at 90° C. for 22 h, whereupon a tlcsample (Al₂O₃-ethyl acetate/THF 9:1) no longer indicates startingmaterial.

[0145] The cooled reaction mixture is treated with ethyl acetate (50 ml)and water (50 ml) and intensively stirred for 15 min. The phases areseparated, the water phase is treated to improve the phase separationwith saturated NaCl solution (50 ml) and extracted with a further 3portions of ethyl acetate (150 ml).

[0146] After this, the water phase is neutralized to pH 7-8 usingsaturated Na₂CO₃ soln (50 ml) and again extracted with ethyl acetate (50ml).

[0147] The ethyl acetate phases are collected and combined, washed withsaturated Na₂CO₃ soln (50 ml) and water (50 ml) and, after drying (K₂CO₃sicc.), concentrated in vacuo. 1.2 g are obtained as a residue, which isdissolved in a little THF and purified by cc (Al₂O₃ (300 g)-ether/THF9:1).

[0148] Fractions 1-30: contain the substance sought, which crystallizesfrom ether/diisopropyl ether, is filtered off with suction and dried:0.6 g.

[0149] Yield: 38%, C₁₉H₁₇ClN₂O₂S, MW=372.88;

[0150]¹H-NMR (CDCl₃:) δ[ppm]=8.54−8.51/7.30−7.28 (AA′BB′; 4H, —pyridyl);6.75/6.53 (AB; 2H,—thiophene, J_((AB))=4 Hz); 4.20−4.04 (m, 4H, CH₂);3.22 (t; J=7.5 Hz, CH₂) 2.59 (quin; J=7.3 Hz, CH₂); 1.17 (t; J=7.1 Hz,CH₃).

EXAMPLE 9B Ethyl3-(5-chloro-2-thienyl)-1-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-2-carboxylate

[0151] From CC purification of example 9A (Al₂O₃-ether/THF 9:1):Fractions 35-60: contains the positional isomer compound, which likewisecrystallizes in pure form from ether/ diisopropyl ether, is filtered offwith suction and dried: 0.11 g.

[0152] Yield: 1.5%, C₁₉H₁₇ClN₂O₂S, MW=372.88;

[0153]¹H-NMR (CDCl₃:) δ[ppm]=8.56−8.53/7.34−7.31(AA′BB′; 4H,—pyridyl);7.03/6.91 (AB; 2H,—thiophene, J_((AB))=4 Hz); 4.17−3.99 (q+t; 4H, CH₂);3.00 (t; J=7.3 Hz, CH₂); 2.545 (quin; J=7.2 Hz, CH₂); 1.07 (t; J=7.1 Hz,CH₃).

EXAMPLE 10A Ethyl5-(4-fluorophenyl)-6-(4-pyridyl)-2,3-dihydropyrrolo-[2,1-b]-thiazole-7-carboxylate

[0154] a) Ethyl thiazolidine-2-carboxylate

[0155] Ethyl glyoxalate (50% in toluene, 40.92 g, 0.2 mol), diluted withtoluene (15 ml), is cooled to 5° C., cysteamine hydrochloride (22.72 g,0.2 mol) is added and a saturated NaHCO₃ solution (8.7% strength, 120ml) is slowly added dropwise (2 h). The temperature is kept below 15° C.during the dropwise addition. The 2-phase system is stirred at RT for 16h.

[0156] The reaction is checked by means of GC: HP17, 10 m, 0.53 mm;

[0157] Temp.: 120° C. (0.5 min), 20° C./min, 180° C. (1 min), inj 220°C., det. 280° C.; rt 2.57.

[0158] After this, the toluene phase is separated off and the aqueousphase (pH 7-8) is extracted with ether (150 ml). Toluene phase and etherphase are dried over Na₂SO₄ (sicc.) and concentrated and the oilyresidues are purified: 26.9 g.

[0159] Yield (crude): 83.5%, C₆H₁₁NO₂S, 161.22 g/mol;

[0160] IR (KBr): 1/λ (cm⁻¹)=3303, 2980, 2939, 1733, 1672, 1516, 1443,1369, 1282, 1182, 1026;

[0161]¹H-NMR (CDCl₃:) δ[ppm]=4.92 (s,1H); 4.25 (q, 2H, J=7.1 Hz); 3.66(m, 1H); 3.10−2.95 (m, 2H); 2.90−2.78 (m, 1H); 2.44 (s, OH ); 1.305 (t,3H, J=7.1 Hz)

[0162] b) Ethyl 3-(4-fluorobenzoyl)thiazolidinecarboxylate

[0163] The solution of ethyl thiazolidine-2-carboxylate (24.18 g, 0.15mol) in abs. CH₂Cl₂ (80 ml) is treated dropwise at RT with the solutionof 4-fluorobenzoyl chloride (23.78, 0.15 mol) in abs. CH₂Cl₂ (20 ml).The solution warms to 38° C., the solvent begins to boil and HCl isreleased. It is kept under reflux for 4 h with heating.

[0164] The CH₂Cl₂ phase is extracted by stirring (30 min) with Na₂CO₃soln (100 ml), washed with water (50 ml) and separated off. It is driedover Na₂SO₄ (sicc.) and concentrated. The residue which remains iscrystallized from diisopropyl ether (30 ml), and the crystals are washedwith diisopropyl ether (25 ml) and dried: 34.07 g.

[0165] Yield: 80.2%, C₁₃H₁₄FNO₃S, MW=283.32;

[0166]¹H-NMR (CDCl₃:) δ[ppm]=7.52 (m; 2H, ar.); 7.17−7.05 (m; 2H, ar.);4.30−4.20 (q; J=7.1 Hz, CH₂); 3.98−3.87 (m; CH₂); 3.32−3.19 (m; 1H);3.09−2.98 (m; 1H); 1.305 (t; J=7.1 Hz, CH₃).

[0167] c) 3-(4-Fluorobenzoyl)thiazolidinecarboxylic acid

[0168] Ethyl 3-(4-fluorobenzoyl)thiazolidinecarboxylate (28.33 g, 0.1mol) is suspended in ethanolic KOH (5% strength, 165 ml, 0.15 mol) andthe mixture is subsequently heated at 50° C. (IT) for 2 h. The cooledsolution is acidified (pH 2-3) with water (100 ml) and dil. phosphoricacid (8%, 150 ml). Precipitated salts are brought into solution again byaddition of water (150 ml). This aqueous solution is extracted withdiethyl ether (500 ml), the ethereal extracts are washed with sat. NaClsolution (100 ml), dried over Na₂SO₄ (sicc.) and concentrated in vacuo.The residue is crystallized from diisopropyl ether (40 ml): 24.87 g.

[0169] Yield: 97.5%, C₁₁H₁₀FNO₃S, MW=255.27;

[0170]¹H-NMR (CDCl₃:) δ[ppm]=8.64 (s; 1H, OH); 7.59−7.53 (m; 2H, ar.);7.19−7.09 (m; 2H, ar.); 5.64 (S; CH); 3.98−3.92 (m; CH₂); 3.36−3.24 (m;CH₂); 3.11−3.01 (m; CH₂)

[0171] d) Ethyl5-(4-fluorophenyl)-6-(4-pyridyl)-2,3-dihydropyrrolo-[2,1-b]-thiazole-7-carboxylate

[0172] The clear solution of 3-(4-fluorobenzoyl)thiazolidine-carboxylate(12.76 g, 0.05 mol) in acetic anhydride (60 ml) obtained at 90° C. istreated with ethyl 2-bromo-3-(4-pyridyl)propenoate (13.8 g, 54 mmol) andstirred at 80° C. (IT) for 4 d. The black-colored reaction mixture isconcentrated in vacuo and, after cooling, treated with MeOH (10 ml).After the reaction is complete, residual acetic anhydride is againconcentrated in vacuo and the residue (30 g) is dissolved completely inMeOH (7 ml) in the presence of heat. Product 10 A crystallizes at RT(TLC: Al₂O₃, ethyl acetate/n-hexane 6:4; rf =0.45). The crystal magma isfiltered off with suction, the crystals are collected (2.6 g) and themother liquor is placed in the cold (0° C.) to obtain a further crystalfraction (2.16 g): 4.42 g (24%)

[0173] After filtration, the mother liquor is diluted with CH₂Cl₂ (20ml) and filtered through a little Al₂O₃. The Al₂O₃ is washed with CH₂Cl₂(150 ml) and the eluates are concentrated: 5.78 g (mixture of product A,rf=0.45 and B, rf=0.5).

[0174] The yellow-colored crystals of the two crystal fractions arewashed with a little cold MeOH and dried:

[0175] Yield: 24%, C₂₀H₁₇FN₂O₂S, MW=368.43;

[0176] IR (KBr): 1/λ (cm⁻¹)=3066, 2992, 2786, 1722, 1692, 1627, 1520,1377, 1226, 1147, 820, 596;

[0177]¹H-NMR (CDCl₃:) δ[ppm]=8.57−8.55/7.33−7.30 (AA′BB′; 4H, —pyridyl);7.47−7.40 (m; 2H, ar.); 7.18−7.10 (m; 2H, ar.); 4.11−3.99 (q+t; 4H,CH₂); 3.69 (t; J=7.0 Hz, CH₂); 0.98 (t; J=7.1 Hz, CH₃).

EXAMPLE 10B Ethyl5-(4-fluorophenyl)-7-(4-pyridyl)-2,3-dihydropyrrolo-[2,1-b]-thiazole-6-carboxylate

[0178] From the mixture (5.78 g) of product A (rf=0.45) and B (rf=0.5)obtained under example 10 A, small fractions of pure product 10 B areobtained by CC on Al₂O₃ using the eluent ethyl acetate/n-hexane (6:4):

[0179] C₂₀H₁₇FN₂O₂S, MW=368.43;

[0180]¹H-NMR (CDCl₃:) δ[ppm]=8.44−8.41/7.36−7.33 (AA′BB′; 4H, ar.);7.11−7.00 (m; 4H, ar.); 4.28−4.15 (m; 4H); 3.77−3.70 (m; 2H); 1.275 (t;CH₃, J=7.1 Hz)

EXAMPLE 115-(4-Fluorophenyl)-6-(4-pyridyl)-2,3-dihydropyrrolo-[2,1-b]-thiazole-7-carboxylicacid

[0181] The compound of example 10 A (1.0 g, 2.7 mmol) is cleavedcompletely (tlc) in 4 h by boiling under reflux in ethanolic KOH (10%,10 ml, 18 mmol). The ethanolic liquor is concentrated in vacuo, thesalt-like residue is taken up in water (40 ml) and the excess of alkaliis neutralized (pH 4-5) using H₃PO₄ (8%) to the extent that thesuspension does not assume a gelatinous consistency. The solid isfiltered off with suction, washed with water and dried over P₂O₅ in anevacuated desiccator for 24 h: 0.87 g of pale yellow powder

[0182] M.p. 210.5° C., yield: 94.6%; C₁₈H₁₃FN₂O₂S, MW=340.38;

[0183] IR (KBr): 1/λ (cm⁻¹)=3399, 1672, 1599, 1534, 1494, 1228, 1160.

[0184]¹H-NMR (d₆-DMSO/CDCl₃): δ[ppm]=8.55−8.52/7.91−7.87 (AA′BB′;2H,—pyridyl); 7.50−7.43 (m, 2H); 7.19−7.10 (m, 2H); 4.14 (t; J=7.1 Hz,CH₂); 3.83 (t; J=7.2 Hz, CH₂);

[0185]¹³C-NMR (d₆,-DMSO/CDCl₃): δ[ppm]=165.3, 164.6, 159.7, 148.5,142.7, 140.2, 134.6, 131.5, 131.4, 130.5, 127.22, 127.15, 122.8, 114.8,114.4, 47.3, 34.4.

EXAMPLE 12[5-(4-Fluorophenyl)-6-(4-pyridyl)-2,3-dihydropyrrolo-[2,1-b]-thiazol-7-yl]methanol

[0186] The compound of example 10 A (0.37 g, 1.0 mmol) is dissolved inabs. THF (7 ml) at 50° C. and kept at 55° C. for 7 h with a solution ofNa bismethoxyethoxyaluminum hydride in toluene (Vitride^(R), 70%strength, 0.80 ml, 2.8 mmol). After cooling, the excess of hydride isdecomposed in an ice bath using a little water and the suspension isstirred until formation of the precipitate is complete. The precipitateis filtered off with suction and washed with water until the reaction ofthe wash phase is neutral: 0.27 g.

[0187] Yield: 82%, C₁₈H₁₅FN₂OS, MW=326.40;

[0188]¹H-NMR (DMSO-d₆/CDCl₃): δ[ppm]=8.76−8.55/7.59−7.55 (AA′BB′;4H,—pyridyl); 7.51−7.44 (m; 2H, ar.); 7.20−7.11 (m; 2H, ar.); 4.49 (s;CH₂); 4.17 (t; J=7.0 Hz, CH₂); 3.73 (t; J=7.0 Hz, CH₂).

EXAMPLE 135-(4-Fluorophenyl)-7-methyl-6-pyridin-4-yl-2,3-dihydropyrrolo-[2,1-b]-thiazole

[0189] The compound of example 12 (2.05 g, 6.3 mmol) is brought intosolution in a mixture of abs. acetonitrile (16 ml), glacial acetic acid(1.6 ml) and a little abs. DMF at 50° C., sodium iodide (2.35 g, 15.7mmol) is added and then trimethylsilyl chloride (TMSCl, 1.6 ml, 1.37 g,12.7 mmol) is added dropwise. The temperature of the batch is kept at50° C. for 2 h. Glacial acetic acid (1.6 ml) and zinc powder (2.87 g, 44mmol) is added in three portions and the mixture is stirred at 80° C.for 16 h. The mixture is cooled, treated with a little water andextracted with CH₂Cl₂. The CH₂Cl₂ extracts are dried over Na₂SO₄ sicc.and concentrated. The residue obtained is taken up in THF and elutedthrough Al₂O₃ (50 g) using THF. From the residue (1.4 g) obtained afterevaporation of the THF, using acetone 0.6 g of pale yellow substance(94%; HPLC: RP 18; acetonitrile/NaH₂PO₄ buffer 70:30) is obtained, whichis recrystallized from MeOH in the presence of heat: 0.43 g of paleyellow powder.

[0190] M.p. 208° C.; yield: 23%, C₁₈H₁₅FN₂S, MW=310.4;

[0191] IR (KBr): 1/λ (cm⁻¹)=1596, 1557, 1533, 1499, 1420, 1361, 1303,1226, 1158, 1098, 1053, 989, 852, 822, 735, 721, 529;

[0192]¹H-NMR (CDCl₃): δ[ppm]=8.57 (2H,—pyridyl); 7.35−7.27(m;4H,—pyridyl and ar.); 7.19−7.10 (m; 2H, ar.); 4.12 (t; J=7.0 Hz, CH₂);3.72 (t; J=7.0 Hz, CH₂); 2.23 (s; CH₃).

[0193]¹³C-NMR (d₆-DMSO/CDCl₃): δ[ppm]=164.6, 159.7, 147.7, 145.2, 132.6,131.0, 130.8, 129.8, 127.5, 121.4, 119.4, 116.0, 115.6, 113.3, 47.9,35.3, 12.8.

EXAMPLE 145-(4-Fluorophenyl)-6-pyridin-4-yl-2,3-dihydropyrrolo-[2,1-b]-thiazole

[0194]5-(4-Fluorophenyl)-6-(4-pyridyl)-2,3-dihydropyrrolo-[2,1-b]-thiazole-7-carboxylicacid (example 11, 120 mg, 0.35 mmol) is heated under argon in an oilbath firstly at 140° C. for 2 h and then at 180° C. for 3 h. Aftercooling to RT, the brown-red melt cake is digested with a little EtOH.The undissolved, red-brown substance is filtered off with suction,washed with ether and dried: 0.07 g.

[0195] Yield: 67%, C₁₇H₁₃FN₂S, MW=296.37;

[0196]¹H-NMR (CDCl₃): δ[ppm]=8.46−8.43/7.64−7.61 (AA′BB′; 4H, —pyridyl);7.44−7.37 (m; 2H, ar.); 7.20−7.11 (m; 2H, ar.); 6.67 (s; CH); 4.35 (t;J=7.2 Hz, CH₂); 3.95 (t; J=7.2 Hz, CH₂).

EXAMPLE 15A Ethyl3-(4-fluorophenyl)-2-(4-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate

[0197] a) 1-(4-Fluorobenzoyl)piperidine-2-carboxylic acid

[0198] D,L-Pipecolic acid (16.15 g, 0.125 mol), dissolved in NaOH (5%,200 ml, 0.25 mol) is treated dropwise at 5° C. (ice-bath cooling) with4-fluorobenzoyl chloride (19.83 g, 0.125 mol), and the magma formingafter 1 h is liquefied using water (50 ml) before further acid chlorideaddition. The batch is stirred at 10-15° C. for 4 h.

[0199] By addition of water (220 ml), the precipitate formed is almostcompletely brought into solution (pH=8-9) and using ether (160 ml) theradicals of the acid chloride and other neutral impurities are removed.The desired product is deposited from the alkaline water phase byaddition of HCl (10% strength) until pH 2 is reached. The HCl-acidicsuspension is extracted with ether (300 ml), and the ether phase isseparated off, dried (Na₂SO₄ sicc.) and concentrated in vacuo. Theresidue (8% 4-fluorobenzoic acid) is crystallized from ether (20 ml):28.67 g.

[0200] Yield: 72%, C₁₃H₁₄FNO₃, MW=251.3;

[0201]¹H-NMR (CDCl₃): δ[ppm]=8.30 ( br; 1H, OH); 7.50−7.35 (m; 2H, ar.);7.20−7.00 (m; 2H, ar.); 5.50 (m; 1H, CH_(X)N); 4.70−4.4 (m; 1H,CH_(A)H_(B)); 3.75−3.60 (m; 1H, CH_(A)H_(B)); 3.35−3.15 (m; 1H,CH_(A)H_(B)); 2.45−2.30 (m; 1H, CH_(A)H_(B)); 1.9−1.3 (m; 4H,CH_(A)H_(B)).

[0202] b) Ethyl3-(4-fluorophenyl)-2-(4-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate

[0203] 1-(4-Fluorobenzoyl)piperidine-2-carboxylic acid (17.6 g, 0.07mol) is dissolved in acetic anhydride (45 ml) at 80° C. and then ethyl2-bromo-3-(4-pyridyl)propenoate (22.4 g, 0.087 mol). A strong evolutionof CO₂ is ended after about 10 min. The reaction mixture is kept at 130°C. (reflux) for 20 h. After cooling, CH₂Cl₂ (100 ml) and water (50 ml)are added and the mixture is vigorously stirred for 10 min, then thephases are separated. The water phase is extracted again with CH₂Cl₂(150 ml), and the combined organic phases are washed until neutral withsat. Na₂CO₃ soln (50 ml), dried (Na₂SO₄ sicc.) and concentrated. 29.26 gof crude product remain. The acidic water phase is alkalized with NaOH,black lumps depositing which are partly soluble in CH₂Cl₂ (200 ml) andcontain residues of the compound sought.

[0204] Residue of this CH₂Cl₂ phase and crude product fraction arecombined (30 g), taken up in CH₂Cl₂ (30 ml) and purified by cc on Al₂O₃(2300 g) using ether/THF (9:1):

[0205] Fractions 4-12: 12.5 g of product 15 A, which crystallizes fromdiisopropyl ether/n-hexane (10 ml, 1:1). The crystals are filtered offwith suction and dried: 9.3 g (36.6%).

[0206] Yield: 9.3 g (36.6%) C₂₂H₂FN₂O₂; MW=364.42.

[0207]¹H-NMR (CDCl₃) δ[ppm]: 8.39−8.36/7.04−7.02 (AA′BB′; 4H,—pyridyl);7.13−6.93 (m; 4H, ar.); 4.12 (q; J=7.11 Hz, CH₂); 3.705 (t; J=3 Hz,CH₂); 3.21 (t; J=2 Hz, CH₂); 1.98−1.85 (m, 2 CH₂, 4H); 1.09 (t; J=7.1Hz, CH₃).

EXAMPLE 15B Ethyl3-(4-fluorophenyl)-1-(4-pyridyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate

[0208] CC purification of the compound from example 15A, b) Separationon Al₂O₃— ether/THF 9:1: fractions 13-19: 2.35 g of substance 15B.

[0209] Crystals from diisopropyl ether/n-hexane (1 ml, 1:1): 1.66 g.

[0210] Yield: 6.6%; C₂₂H₂₁FN₂O₂; MW=364.42.

[0211]¹H-NMR (d6-DMSO) δ[ppm]=: 8.50−8.45 (AA′, 2 H, pyridinyl);7.45−7.37 (m, 2H , ar.); 7.30−7.15 (m, 4H, ar.+BB′ pyridinyl); 3.80 (q,2H, J=7.0 Hz, OCH2); 3.65−3.55 (m, 2H, CH₂ ); 2.75−2.65 (m, 2H CH₂);1.80−1.60 (m, 4H, CH₂—CH₂) 0.757 (t, 3H, J=7.0 Hz, CH₃).

[0212]¹³C-NMR (CDCl₃): δ[ppm]=164.10, 162.09 (d, J=243.4 Hz), 148.80,143.29, 135.61, 132.840 (d, J=8.4 Hz), 128.58, 127.816 (d, J=3.3 Hz),124.91, 117.61, 114.91 (d, J=21.4 Hz), 111.33, 58.96, 44.35, 22.71,22.34, 19.93, 13.52.

EXAMPLE 16[3-(4-Fluorophenyl)-2-(4-pyridyl)-5,6,7,8-tetrahydroindolizine-1-yl]methanol

[0213] The solution of ethyl3-(4-fluorophenyl)-2-(4-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate(example 15 A, 2.55 g, 7 mmol) in abs. THF (15 ml) is treated dropwiseunder argon at RT with the solution of NaAlH₂(OC₂H₄OCH₃)₂ in toluene(Vitride^(R) 70%, 2.9 ml, 10 mmol) and the batch is stirred at 40° C.for 24 h until the complete disappearance of the starting material (tlcAl₂O₃/ethyl acetate: starting material rf=0.8; product rf=0.5). Theexcess of hydride is destroyed by addition of water (2 ml), then THF isremoved in vacuo and the residue is taken up in ethyl acetate. The ethylacetate phase is washed with water until the reaction of the wash phasesis neutral (60 ml). The ethyl acetate phase is dried over Na₂SO₄ sicc.and concentrated: a residue of 2.15 g remains.

[0214] Yield: 95%; C₂₀H₁₉FN₂O; MW=322.4.

[0215] IR (KBr): 1/λ (cm⁻¹)=3243, 2946, 1600, 1534, 1511, 1221, 994,840, 579;

[0216]¹H-NMR (CDCl₃) δ[ppm]=8.40−8.37/7.15−7.12 (AA′BB′; 4H,—pyridyl);7.17−7.12 (m; 2H, ar.); 7.07−6.98 (m; 2H, ar.); 4.55 (s; CH₂); 3.80−3.70(m; CH₂); 3.00−2.90 (m; CH₂); 1.95−1.90 (m; 4H, CH₂).

EXAMPLE 173-(4-Fluorophenyl)-1-methyl-2-(4-pyridyl)-5,6,7,8-tetrahydroindolizine

[0217] The mixture of[3-(4-fluorophenyl)-2-(4-pyridyl)-5,6,7,8-tetrahydroindolizin-1-yl]methanol(example 16, 3.52 g, 11 mmol) with hydriodic acid (57%, 20 ml, 0.15 mol)is heated to 100° C. and the course of the reaction is checked by tlc(Al₂O₃, ether). After 45 min, starting material (rf=0.2) is no longerdetectable (product: rf=0.7).

[0218] The cooled reaction mixture is treated with ethyl acetate (100ml), extracted by shaking with sat. Na₂CO₃ solution and decolorizedusing Na₂S₂O₃ solution and then washed with water. The ethyl acetatephase is dried over Na₂SO₄ sicc. and concentrated. The residue ispurified by cc (Al₂O₃, ether/THF 9:1): fraction 4-11 yields 1.6 g ofproduct, which crystallizes from diisopropyl ether: 1.02 g

[0219] Yield: 30.4%; C₂₀H₁₉FN₂; MW=306.4.

[0220]¹H-NMR (CDCl₃) δ[ppm]=8.40−8.36/7.00−6.97 (AA′BB′, 4H,—pyridyl);7.18−7.11 (m; 2H, ar.); 7.04−6.96 (m; 2H, ar.); 3.75−3.70 (m; CH₂);2.83−2.78 (m; CH₂); 2.08 (S; 3H, CH₃) 1.95−1.85 (m; 4H, CH₂-CH₂);

[0221]¹³C-NMR (CDCl₃): δ[ppm]=164.5, 159.6, 149.1, 144.5, 132.6, 132.4,128.6, 128.2, 128.1, 126.9, 124.6, 119.9, 115.7, 115.3, 11.9, 44.4,23.8, 22.0, 20.9.

EXAMPLE 18 3-(4-Fluorophenyl)-2-(4-pyridyl)-5,6,7,8-tetrahydroindolizine

[0222] Ethyl3-(4-fluorophenyl)-2-(4-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylate(example 15A, 2.92 g, 8 mmol) and hydriodic acid (57%, 16.0 ml, 27 g,120 mmol) are mixed at 60° C. and maintained at a temperature of 120° C.The initially deposited hydriodide dissolves again in the presence ofheat (10 min). The course of the reaction is checked by tlc (Al₂O₃,ether/THF 9:1). After 30 min, the conversion is complete (startingmaterial rf=0.6; product rf=0.8). The mixture is cooled in an ice bath.

[0223] The precipitate of the crystallized hydriodide formed is filteredoff with suction, purified of adherent HI by washing with water (6 times5 ml) and dried in vacuo (desiccator, P₂O₅). 2.68 g (79.5%) ofhydriodide are isolated.

[0224] The mother liquor of the crystallization is neutralized usingNaOH and extracted with ethyl acetate. The ethyl acetate phase isdecolorized using Na₂S₂O₃ solution and then washed with water. The ethylacetate phase is dried over Na₂SO₄ sicc. and concentrated: 0.44 g ofproduct (base).

[0225] Isolation of the Base:

[0226] 5-(4-Fluorophenyl)-6-(4-pyridyl)-2,3-dihydro-1H-pyrrolizinehydriodide (2.68 g, 9.2 mmol) is suspended in CH₂Cl₂ (150 ml) andintensively stirred with saturated NaHCO₃ solution (40 ml). The CH₂Cl₂phase is then separated off, dried using Na₂SO₄ sicc. and concentratedin vacuo to a small volume (5 ml). The crystals formed are washed withdiisopropyl ether and dried: 1.66 g.

[0227] Yield: 72.2%, C₁₉H₁₇FN₂; MW=292.36

[0228]¹H-NMR (CDCl₃) δ[ppm]=8.32−8.29/7.01−6.98 ( AA′BB′, 4H, —pyridyl);7.30−7.21 (m; 2H, ar.); 7.16−7.06 (m; 2H, ar.); 6.21(s; 1H);3.70−3.64(m, CH₂); 2.91−2.85 (m; CH₂); 1.98−1.80 (m; 4H, CH₂—CH₂);

[0229]¹³C-NMR (CDCl₃): δ[ppm]=165.0, 160.1, 149.3, 144.2, 132.8, 132.6,130.4, 126.1, 128.5, 128.4, 121.6, 119.2, 116.1, 115.7, 104.2, 44.3,23.6, 23.4, 20.9.

EXAMPLE 19A Ethyl2-(4-fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0230] a) Benzyl 1-(pyridine-4-carbonyl)pyrrolidine-2-carboxylate

[0231] L-Proline benzyl ester hydrochloride (2.42 g, 0.01 mol) dissolvedin pyridine (80 ml) is treated in portions at 3° C. (ice-bath cooling)with isonicotinoyl chloride hydrochloride (1.78 g, 0.01 mol), the ITincreasing to 10° C. After removing the ice bath, the mixture is stirredfor 5 h, the batch turning greenish.

[0232] Excess pyridine is removed on a Rotavapor and the residueobtained is partitioned between water (40 ml) and ether. Afterseparating off the ether phase, the water phase is extracted with ether(60 ml). The ether phases are collected, washed with water (20 ml),dried (Na₂SO₄ sicc.) and concentrated in vacuo. The residue is dried ina high vacuum: 2.96 g.

[0233] Yield: 85%, C₁₈H₁₈N₂O₃, MW=310.36;

[0234]¹H-NMR (CDCl₃): δ[ppm]=8.72−8.69/7.43−7.40 (AA′BB′, 4H, —pyridyl);7.37 (s; 5H); 5.260/5.188 ( AB, J_(AB)=12.3 Hz, OCH₂Ph); 4.765−4.695 (m,CH_(X), 1H); 3.610−3.395 (m, 2H, CH_(A)H_(B)); 2.140−1.875 (m, 4H, CH₂—CH_(A) H _(B)—CH_(X)).

[0235] b) 1-(Pyridine-4-carbonyl)pyrrolidine-2-carboxylic acid

[0236] Benzyl 1-(pyridine-4-carbonyl)pyrrolidine-2-carboxylate (4.0 g,11.5 mmol) is dissolved at RT in a mixture of THF and ethanol abs. (1:1,30 ml), and treated with palladium on active carbon (10%, 0.7 g).Evacuation is then carried out three times and the vacuum is replaced byhydrogen from a balloon. The mixture we hydrogenated at atm and RT for16 h. After this, the reaction mixture no longer contains startingmaterial (tlc Al₂O₃/n-hexane ethyl acetate (1:1); starting material:rf=0.2-0.4 and product: rf=0.0).

[0237] The product solution is removed from the catalyst (G4),concentrated in vacuo and dried in a high vacuum, 2.95 g (>100%),content according to gc about 60% strength.

[0238] c) Ethyl 2-bromo-3-(4-fluorophenyl)propenoate

[0239] With exclusion of light,bromocarbethoxymethylenetriphenyl-phosporane (example 1A, b; 9.0 g, 21mmol) is brought into solution in toluene (60 ml) and and the solutionof 4-fluorobenzaldehyde (2.48 g, 20 mmol) in toluene (9 ml) is thenadded. The solution is stirred at RT for 16 h in the dark, concentratedin vacuo, the residue is treated with ether (40 ml) and the crystalsdeposited in the course of this are washed with ether (2×10 ml).

[0240] The collected ether solutions are concentrated in vacuo and theresidue which remains (7.82 g) is treated with an ether/n-hexane mixture(1:1, 5 ml). Precipitate remaining undissolved during this is separatedoff and washed with ether/n-hexane mixture (1:1). On concentrating, 6.06g of the residue still remain here which are purified by cc (SiO₂,ether/n-hexane 1:1): The substance sought appears in the fractions 1-2:yellow-brown oil, 4.72 g.

[0241] Yield: 99. 6%; C₁₁H₁₀BrFO₂; MW=273.10.;

[0242] IR (NaCl): 1/λ (cm⁻¹)=2983, 1724, 1601, 1508, 1261, 1235, 1195,1161, 1040, 833;

[0243]¹H-NMR (CDCl₃:) δ[ppm]=8.18 (s; 1H); 7.91−7.84 (m, 2H, ar.)7.16−7.07 (m; 2H, ar.) 4.36 (q; J=7.2 Hz, CH₂); 1.38 (t; J=7.1 Hz, CH₃);

[0244]¹³C-NMR (CDCl₃:) δ[ppm]=163.4 (d, J=250 Hz), 163.2, 139.4, 138.7,132.4 (d, J=9 Hz), 129.9, 115.55 (d, 24 Hz), 112.9, 62.7, 15.1.

[0245] d) Ethyl2-(4-fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0246] A mixture of 1-(pyridine-4-carbonyl)pyrrolidine-2-carboxylic acid(example 19A, b; 60%, 1.5 g, 4.1 mmol), ethyl2-bromo-3-(4-fluorophenyl)propenoate (example 19A, c; 1.0 g, 4 mmol) andacetic anhydride (10 ml) are heated under reflux for 21 h in an oil bathmaintained at a temperature of 150° C. After cooling and concentratingin vacuo (Rotavapor), needles deposit. The concentrated crystalsuspension is treated with ether/ethyl acetate (1:2) and the crystalsare filtered off with suction. The mother liquor is completelyconcentrated and the residue is purified by cc (Al₂O₃— ether/THF 9:1):

[0247] Fractions 3-5: product 19 A, which crystallizes from ether. Thecrystals are filtered off with suction and dried: 0.12 g.

[0248] Yield: 8.5%, C₂₁H₁₉FN₂O₂; MW=350.4.

[0249]¹H-NMR (CDCl₃) δ[ppm]=8.45−8.42/6.97−6.94 (AA′BB′; 4H,—pyridyl);7.23−7.15/7.02−6.93 (AA′BB′; 4H, ar.); 4.20−4.09 (q, CH₂O;+t, CH₂, 4H);3.23 (t; J=7.5 Hz, 2H); 2.58 (quin; J=7.2 Hz, 2H, CH₂); 1.18 (t; J=7.1Hz, CH₃)

EXAMPLE 19B Ethyl1-(4-fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-2-carboxylate

[0250] CC purification of the compound from example 19A, d) Separationon Al₂O₃-ether/THF 9:1: fractions 7-20, crystals from ether: 0.05 g.

[0251] Yield: 3%; C₂₁H₁₉FN₂O₂; MW=350.4.

[0252]¹H-NMR (CDCl₃) δ[ppm]=8.67−8.64/7.40−7.37 (AA′BB′; 4H, pyridyl);7.39−7.32/6.98−6.93 (m; 4H, ar.); 3.97 (t; 2H, J=7.1 Hz); 2.94 (t; 2H,J=7.2 HZ); 2.62−2.48 (m; 2H); 0.975 (t; J=7.1 Hz, CH₃).

EXAMPLE 20[2-(4-Fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-yl]methanol

[0253] Ethyl2-(4-fluorophenyl)-3-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate(example 19A, 0.15 g, 0.43 mmol) is dissolved under argon in abs. THF (4ml) and sodium dihydridobis(2-methoxy-ethoxy)aluminate solution (Vitride^(R), 70% in toluene, 0.9 ml, 4.5 mmol) is added dropwise in 4 portionsat 40° C. with exclusion of moisture at in each case an interval of 1hour. 1 h after the last addition, starting material can no longer bedetected by tlc (Al₂O₃— ethyl acetate/n-hexane 3:7). After this, themixture is allowed to cool. The reaction solution is partitioned betweenwater (20 ml) and ethyl acetate (20 ml) and the water phase isneutralized to pH 6-7 by means of HCl (3%). The phases are separated andthe water phase is extracted 3 times by shaking with ethyl acetate (20ml). The combined organic phase is dried over Na₂SO₄ sicc andconcentrated in vacuo: 0.21 g.

[0254] Yield: >100%; C₁₉H₁₇FN₂O; MW=308.36.

[0255]¹H-NMR (CDCl₃): δ[ppm]=8.41−8.38/7.05−7.01 (AA′BB′; 4H, —pyridyl);7.26−7.20 (m; 2H, ar.); 7.04−6.97 (m; 2H, ar.); 4.47 (S; CH₂O); 4.12 (t;J=7.0 Hz, CH₂N); 3.01 (t; J=7.3 Hz, CH₂); 2.57 (quin; J=7.5 Hz, 2H,CH₂).

EXAMPLE 216-(4-Fluorophenyl)-7-methyl-5-(4-pyridyl)-2,3-dihydro-1H-pyrrolizine

[0256] a) 2-Ethyl-1-pyrroline

[0257] Sodium hydride (60% in paraffin, 36 g, 0.9 mol) in abs. THF (180ml) is suspended in a 1 l 3-necked flask having a dropping funnel andreflux condenser and the suspension is heated with gentle refluxing for10 min. The mixture of ethyl propionate (33.7 g, 0.33 mol) and1-vinyl-2-pyrrolidone (33.34 g, 0.3 mol) in abs. THF (35 ml) are addeddropwise to the boiling suspension (10 min) and kept under reflux byheating for 3.5 h with stirring.

[0258] After cooling to 10° C. (ice bath) the excess of sodium hydrideis destroyed and neutralized using sat. ammonium chloride solution (300ml) (beware! H₂) and to drive off the ammonia liberated the now warmmixture (30° C.) is intensively stirred for a further 10 min. Thedeposited THF phase is separated off, dried over Na₂SO₄ sicc. andconcentrated. The paraffin layer depositing on the oil phase isdecanted. The red, oily product fraction obtained(3-propionyl-1-vinyl-2-pyrrolidone, 51.2 g, about 92%) is used withoutfurther purification for the preparation of 2-ethyl-1-pyrroline:

[0259] B.p.=140.20° C. (760 torr), yield: 102%, C₉H₁₃NO₂, MW=167.21.

[0260] IR (NaCl): 1/λ (cm⁻¹)=2955, 2925, 2854, 1698, 1633, 1456, 1427,1387, 1327, 1273, 1114, 979;

[0261]¹HNMR (CDCl₃): d (ppm)=7.08−6.95 (CH); 4.52−4.42 (CH₂) 3.74−3.67(CH); 3.60−3.41 (CH₂); 3.13−2.96 (CH); 2.69−2.51 (CH₂); 2.23−2.09 (CH);1.08 (t, J=7 Hz, CH₃).

[0262]¹³CNMR (CDCl₃): d (ppm)=205.3 (C=O), 168.4 (C=O), 129.1 (C—H),95.6 (CH₂), 55.2 (C—H), 43.1 (CH₂), 35.9 (CH₂), 19.3 (CH₂), 7.3 (CH₃)

[0263] HCl (20%, 300 ml) is heated to gentle boiling in a 3-necked flaskhaving a dropping funnel and water separator with reflux condenser. Asolution of the crude 3-propionyl-1-vinyl-2-pyrrolidone (40.4 g, 240mmol) in THF (60 ml) is added dropwise from the dropping funnel (10 min)and the batch mixture is kept at 100° C. (IT). The acetaldehyde/THFmixture (47 ml) collected in the water separator is discarded. Themixture is kept at this temperature for 6 h, cooled and extracted withether (200 ml). The 2-ethyl-1-pyrroline is deposited from the HCl-acidicwater phase by alkalization to pH 9-10 in the cold (5-10° C.). Thedeposited oil is taken up in diethyl ether (150 ml) and the water phaseis extracted with diethyl ether (300 ml). The ether phases are combined,dried (K₂CO₃) and concentrated in a weak vacuum (240 mmHg, 45° C.). 18.4g of 2-ethyl-1-pyrroline are obtained as a yellow-colored oil (about94%).

[0264] B.p.=109.5 (760 mmHg); yield: 79%, C₆H₁₁N, MW=97.16.

[0265] IR (NaCl): 1/λ (cm⁻¹) 3378, 2969, 2937, 2870, 1644, 1462, 1454,1431, 1371, 1300, 1144, 1093, 1019, 961;

[0266]¹HNMR (CDCl₃): d (ppm)=3.38-3.76 (m; CH₂); 2.52−2.34 (m; 2 CH₂);1.89 (quin.; CH₂, J=7.8 Hz); 1.15 (t; CH₃, J=7.6 Hz);

[0267]¹³CNMR (CDCl₃): d (ppm)=179.8, 60.5, 36.9, 26.8, 22.4, 10.6.

[0268] b) 6-(4-Fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine

[0269] 2-Bromo-1-(4-fluorophenyl)-1-ethanone (19.53 g, 90 mmol) is addedto the oily ethyl-1-pyrroline (17.55 g, 180 mmol) in portions in a 500ml flask, the exothermically reacting mixture cooling between theadditions. The mixture of the reaction components is heated in an oilbath (100° C.) with stirring (30 min). The course of the reaction ismonitored by tlc.

[0270] The cooled mixture is treated with CH₂Cl₂ (250 ml) and depositedsalts are washed out in a separating funnel using two portions of HCl(3%, 40 ml). The CH₂Cl₂ phase is washed with water (50 ml), dried(Na₂SO₄ sicc.) and concentrated.

[0271] As a residue, 14.04 g of6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine remain as a brownviscous oil (about 90%).

[0272] Yield: 72%; C₁₄H₁₄FN, MW=215.27.

[0273]¹HNMR (CDCl₃): d (ppm)=7.39−7.30 (m, 2H, F-ar.); 7.08−6.98 (m, 2H,F-ar.); 6.67 (s, 1H, 5-H); 3.954 (t; 2H, CH₂, J=7 Hz); 2.801 (t; 2H,CH₂, J=7 Hz); 2.487 (quin.; CH₂, J=7 Hz); 2.125 (s; 3H, CH₃)

[0274]¹³CNMR (CDCl₃): d (ppm)=161.04 (d, C—F, J=242 Hz), 135.58 (d,J=2.0 Hz), 133.51 (d, J=2 Hz), 128.87 (d, J=7.5 Hz); 127.65; 115.025 (d,J=20.9 Hz); 111.11 (pyrrole-C—H); 106.71; 46.47; 27.44; 23.14; 10.86.

[0275] c) Ethyl4-[2-(4-fluorophenyl)-1-methyl-6,7-dihydro-5H-pyrrolizine-3-yl]-4H-pyridine-1-carboxylate

[0276] The solution of6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine (1.72 g, 8.0mmol) in CH₂Cl₂ (55 ml) is firstly treated at 0° C. (ice bath) withpyridine (1.6 ml, 1.58 g, 20 mmol) and dropwise with the solution ofethyl chloroformate (2.1 g, 19.5 mmol) in CH₂Cl₂ (25 ml) (10 min). Aftera temperature rise to 3-6° C., the cooling agent is removed and themixture is stirred for 1 h at RT, then heated to boiling temperature(36° C.) for 15 min. Then and after refluxing for a further hour, ineach case 2 further portions of pyridine (each 0.8 ml, 10 mmol) andchloroformic acid (each 1.05 g, 10 mmol) are added dropwise and after atotal of 3 h the reaction is terminated. The dark-colored batch solutionis poured onto ice water (100 ml), stirred for 15 min and then thephases are separated. The water phase is extracted with CH₂Cl₂ (100 ml)and the combined organic phase is washed with water (50 ml), dried(Na₂SO₄ sicc.) and concentrated. As a residue, 2.69 g of dark oil (91.9%crude) remain which still contains residues of unreacted6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine and was employedwithout further purification in the next stage.

[0277] Yield: 91%; C₂₂H₂₃FN₂O₂; MW=366.44.

[0278] d)6-(4-Fluorophenyl)-7-methyl-5-(4-pyridyl)-2,3-dihydro-1H-pyrrolizine

[0279] Potassium tert-butoxide (3.36 g, 30 mmol) is added to thesolution of the dihydropyridine compound from example 21,c (1.83 g, 5mmol) in tert-butanol (30 ml) obtained at RT, and the mixture is firstlyintensively stirred with admittance of air for 1 h at RT, then underreflux for 1 h. The solution is concentrated, and the residue is takenup with water (40 ml) and extracted with ethyl acetate (100 ml). Theethyl acetate phase is washed with water (20 ml), dried (Na₂SO₄ sicc.)and concentrated. The attempt to crystallize this residue (1.03 g) fromether (3 ml) was not successful.

[0280] The purification of the substance was carried out by cc (Al₂O₃,ether):

[0281] The residue obtained from fractions 33-42 crystallizes fromether: 0.14 g.

[0282] Yield: 10%; C₁₉H₁₇FN₂; MW=292.36

[0283]¹H-NMR (CDCl₃) δ[ppm]=8.40−8.37/7.00−6.97 (AA′BB′; 4H,—pyridyl);7.20−7.11 (m; 2H, ar.); 7.06−6.96 (m; 2H, ar.); 4.10 (t; J=7.0 Hz, CH₂);2.885 (t; J=9.4 Hz, CH₂); 2.54 (quin; J=7.1 Hz, CH₂), 1.99 (s; CH₃).

EXAMPLE 22 6-(4-Fluorophenyl)-5-(4-pyridyl)-2,3-dihydro-1H-pyrrolizine

[0284] a) 1-Fluoro-4-(2-nitrovinyl)benzene

[0285] The mixture of 4-fluorobenzaldehyde (12.4 g, 0.1 mol), anhydrousammonium acetate (7.8 g, 0.101 mol) and nitromethane (8.1 ml, 9.15 g,0.15 mol) in glacial acetic acid (68 ml) are heated to reflux (110° C.)for 3.5 h. The cooled mixture is treated with ice water (80 ml),whereupon brown needles crystallize out. After placing in the cold in anice bath for 30 min, the crystals are filtered off with suction, washedwith water (60 ml) and dried for 16 h in vacuo (desiccator) over P₂O₅:13.2 g (81.8%).

[0286] The crystals are recrystallized from acetic acid (50%, 130 ml) inthe presence of heat: the slightly pale green crystals crystallizing inthe cold (2 fractions) are washed with water (60 ml) and dried as above:9.76 g, and 1.09 g.

[0287] Yield: 67% (10.8 g), C₈H₆FNO₂; MW=167.14

[0288] IR (KBr): 1/λ (cm⁻¹)=3111, 1637, 1595, 1501, 1341, 1230, 1164,965, 827, 515;

[0289]¹H-NMR (CDCl₃): δ[ppm]=8.02−7.96 (d, 1H, J=13.7 Hz, —C_(b)H═CH_(a)NO₂); 7.60−7.50 (m, 3H, ar.+—C_(b) H═CH_(a)NO₂); 7.20−7.11 (t,2H, J=8.5 Hz, ar.).

[0290] b) 6-(4-Fluorophenyl)-5-(4-pyridyl)-2,3-dihydro-1H-pyrrolizine

[0291] 1-(Pyridine-4-carbonyl)pyrrolidine-2-carboxylic acid (example19A, b; 60%, 2.0 g, 5.5 mmol) dissolved at 80° C. in acetic anhydride(16 ml) is treated with 1-fluoro-4-(2-nitrovinyl)-benzene (1.32 g, 7.9mmol) and heated to 130° C. (IT). At 110° C. begins the release of NO₂and CO₂, which is complete after 60 min. After a total of 2 h at110-130° C., the batch is allowed to cool and to stand at RT for 16 h.

[0292] The mixture is partitioned between water (70 ml) and ethylacetate (50 ml), the organic phase is separated off, the H₂O phase isextracted with ethyl acetate (100 ml) and the combined ethyl acetatephase is dried (Na₂SO₄ sicc.) and concentrated.

[0293] The isolation of the product was carried out by means of CC(Al₂O₃, ether): fractions 17-60, (rf=0.5): residue crystallizes fromdiisopropyl ether, 0.32 g (needles, 2nd crystallization fraction fromthe mother liquor 0.1 g).

[0294] Yield: 16.6% (0.32 g), C₁₈H₁₅FN₂; MW=278.33

[0295] IR (KBr): 1/λ (cm⁻¹)=3111, 1637, 1595, 1501, 1341, 1230, 1164,965, 827, 515;

[0296]¹H-NMR (CDCl₃) δ[ppm]=8.49−8.45/7.13−7.10 (AA′BB′; 4H,—pyridyl);7.25−7.17 (m; 2H, ar.); 6.99−6.90 (m; 2H, ar.) 6.03 (s; H,pyrrolizine-C5-H); 4.06 (t; J=7.0 Hz, CH₂); 2.95 (t; J=7.3 Hz, CH₂);2.54 ( quin; J=7.2 Hz, CH₂);

[0297]¹³C-NMR (CDCl₃): δ[ppm]=164.0, 159.2, 150.0 140.6, 139.6, 132.8,132.7, 130.1, 130.0, 128.3, 122.8, 115.6, 115.2, 120.1, 46.9, 27.5,24.5.

EXAMPLE 237-(4-Fluorophenyl)-3,3-dimethyl-8-pyridin-4-yl-3,4-dihydro-2H-pyrrolo[2,1-b][1,3]thiazine

[0298] a) 4-(4-Fluorophenyl)-3-pyridin-4-yl-5H-furan-2-one

[0299] A solution of K tert-butoxide (33.7 g, 0.3 mmol) in MeOH (220ml), which is prepared with ice cooling, is added dropwise to asuspension of 4-pyridylacetic acid hydrochloride (25.9 g, 0.15 mol) inanhydrous MeOH (150 ml). After stirring at RT for 1 h, the methanol isdistilled off in vacuo and the residue of the potassium salts is takenup in DMF abs. (250 ml). 2-Bromo-1-(4-fluorophenyl)ethanone (23.9 g,0.11 mol) is stirred in in portions (5 g) and stirring of the mixture iscontinued at RT for 2 h. After this, it is poured onto water (1.5 l) andextracted by stirring with CHCl₃ (250 ml) for 30 min and the CHCl₃ phaseis separated off in a separating funnel. The water phase separated offis extracted with CHCl₃ (300 ml), and the combined CHCl₃ extracts arewashed with water (200 ml), dried over Na₂SO₄ sicc. and concentrated.The dark-green semicrystalline residue is digested with EtOH (50 ml),and the crystals are filtered off with suction, washed with EtOH (20 ml)and dried: 18.8 g of yellow-green crystals.

[0300] M.p. 157.0° C.; yield: 50%, C₁₅H₁₀FNO₂; MW=255.25;

[0301] IR (KBr): 1/λ (cm⁻¹)=1746, 1647, 1602, 1509, 1233, 1161, 1037,827, 839;

[0302]¹H-NMR (CDCl₃): δ[ppm]=8.68−8.64 (m, 2H, AA′ pyridyl.); 7.38−7.26(m, 4H, BB′ pyridyl.+F-ar.); 7.14−7.05 (m, 2H, F-ar.); 5.19 (s, 2H,CH₂);

[0303] b)4-(4-Fluorophenyl)-1-(3-hydroxy-2,2-dimethyl-propyl)-3-pyridin-4-yl-1,5-dihydropyrrol-2-one

[0304] Equimolar amounts of neopentanolamine(3-hydroxy-2,2-dimethyl-propylamine, 36.3 g, 0.35 mol) and glacialacetic acid (21.0 g, 0.35 mol) are homogeneously mixed with evolution ofheat and the still warm mixture is heated to 105° C. (IT) by lowering itinto a temperature-controlled oil bath.4-(4-Fluorophenyl)-3-pyridin-4-yl-5H-furan-2-one (17.8 g, 0.07 mol) isstirred into this neopentanolammonium acetate melt in 4 portions (15min) and the reaction mixture is heated for a further 1.5 h. The cooledreaction mixture is treated with sat. NaHCO₃ solution and ethyl acetate(50 ml) and intensively stirred (30 min). The crystals deposited arefiltered off with suction, washed with ethyl acetate and dried in vacuo:12.3 g.

[0305] Yield: 52%, C₂₀H₂₁FN₂O₂; MW=340.40

[0306] IR (KBr): 1/λ (cm⁻¹)=3410, 1662, 1598, 1506, 1381, 1228, 1049,831;

[0307]¹H-NMR (CDCl₃) δ[ppm]=8.63−8.59 (m, 2H, AA′ pyridyl.); 7.351−7.225 (m, 4H, BB′ pyridyl.+F-ar.); 7.085−6.995 (m, 2H, F-ar.); 4.44 (s,2H, C-5-CH ₂); 3.40 (s, 2H, CH₂OH); 3.27 (br, 2H, CH₂N); 1.88 (br, OH),1.00 (s, 6H, CH₃).

[0308] c) 7-(4-Fluorophenyl)-3,3-dimethyl-8-pyridin-4-yl-3,4-dihydro-12H-pyrrolo[2,1-b][1,3]-thiazine

[0309]4-(4-Fluorophenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-3-pyridin-4-yl-1,5-dihydropyrrol-2-one(5.1 g, 15 mmol) and phosphorus pentasulfide (P₂S₅, 2.5 g, 11.2 mmol)are intimately triturated and the trituration is then heated at 210° C.under argon in an oil bath for 3 h. The solidified glassy mass isdissolved in ethyl acetate (40 ml) and NaOH (10%, 40 ml). The ethylacetate phase is separated off, washed with water, dried (Na₂SO₄ sicc.)and concentrated. The residue (3.8 g) is purified by cc (SiO₂/ethylacetate):

[0310] The residue obtained from fraction 2 (rf=0.9) crystallizes fromdiisopropyl ether: 0.6 g.

[0311] Yield: 11.8%, C₂₀H₁₉FN₂S; MW=338.45

[0312] IR (KBr): 1/λ (cm⁻¹)=3432, 1964, 1597, 1535, 1498, 1385, 1212,1164, 991, 840, 816, 591, 517;

[0313]¹H-NMR (CDCl₃) δ[ppm]=8.465−8.430 (m, 2H, AA′ pyridyl.);7.262−7.05 (m, 4H, BB′ pyridyl.+F-ar.); 7.00−6.935 (m, 2H, F-ar.); 6.71(s, 1H, CH═); 3.70 (s, 2H, CH₂); 2.80 (s, 2H, CH₂); 1.22 (s, 6H,C(CH₃)₂);

[0314] GC-MS (EI, 70 eV): m/z (rel Int. [%])=340 (9), 339 (28), 338(100), 282 (8), 281 (30).

EXAMPLE 247-(4-Fluorophenyl)-3,3-dimethyl-8-pyridin-4-yl-3,4-dihydro-2H-pyrrolo[2,1-b][1,3]-oxazine

[0315]4-(4-Fluorophenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-3-pyridin-4-yl-1,5-dihydropyrrol-2-one(example 23, b; 2.55 g, 7.5 mmol) dissolved in CH₂Cl₂ (30 ml) is treatedwith pyridine (2.82 g, 35.6 mmol) and then dropwise with methanesulfonylchloride (3.84 g, 33.8 mmol) and the mixture is stirred at RT for 16 h.Water (20 ml) is added and after stirring for 15 min the phases areseparated in a separating funnel. The CH₂Cl₂ phase is firstly washeduntil neutral with sat. NaHCO₃ soln (10 ml), dried over Na₂SO₄ sicc. andconcentrated. The residue obtained (1.9 g, 51%) of thedimethanesulfonate (+monomethane-sulfonate) is taken up in methanolicKOH (25 ml, 2N) and heated to reflux under argon for 16 h. After this,it is diluted with semisaturated sodium chloride solution (150 ml) andextracted with ethyl acetate. The ethyl acetate extracts are dried overNa₂SO₄ sicc. and concentrated. The residue (0.8 g) is crystallized fromdiisopropyl ether, and the crystals are filtered off with suction anddried in vacuo: 0.3 g of crystals.

[0316] M.p. 173.0° C., yield: 12.4%, C₂₀H₁₉FN₂O; MW=322.39

[0317] IR (KBr): 1/λ (cm⁻¹)=2962, 2870, 1599, 1549, 1505, 1389, 1217,1142, 1006, 992, 823, 835, 809, 580;

[0318]¹H-NMR (CDCl₃) δ[ppm]=8.371−8.340 (m, 2H, AA′ pyridyl.);7.262−7.10 (m, 4H, BB′ pyridyl.+F-ar.); 7.05−6.90 (m, 2H, F-ar.); 6.19(s, 1H, CH═); 3.95 (s, 2H, CH₂); 3.71 (s, 2H, CH₂); 1.185 (s, 6H,C(CH₃)₂);

[0319] GC-MS (70 eV) m/e=322(100%); 293(>10%), 238.

1. A 4-pyridyl- or 2,4-pyrimidinyl-substituted pyrrole derivative andits use in pharmacy, of the formula

in which one of the radicals R¹, R² and R³ is 4-pyridyl, 2,4-pyrimidylor 3-amino-2,4-pyrimidyl, which is optionally substituted by one or twoC₁-C₄-alkyl groups or halogen atoms, the second of the radicals R¹, R²and R³ is phenyl or thienyl, which is optionally substituted by one ortwo C₁-C₄-alkyl groups or halogen atoms, and the third of the radicalsR¹, R² and R³ is H, CO₂H, CO₂C₁-C₆-alkyl, CH₂OH or C₁-C₆-alkyl, R⁴ andR⁵ independently of one another are H or C₁-C₆-alkyl; X is CH₂, s or Oand n is 1 or 2, and the optical isomers, physiologically tolerablesalts and physiologically easily hydrolyzable esters thereof.
 2. Acompound of the formula I as claimed in claim 1, where the second of theradicals R¹, R² and R³ is fluorine- or chlorine-substituted phenyl orthienyl.
 3. A compound of the formula I as claimed in claim 1, where thesecond of the radicals R¹, R² and R³ is 4-fluorophenyl or5-chlorothien-2-yl.
 4. A compound of the formula I as claimed in one ofthe preceding claims, where the third of the radicals R¹, R² and R³ isCO₂H.
 5. A compound of the formula I as claimed in claim 1, in which thevariables have the following meanings:

X n R¹ R² R³ R⁴ R⁵ CH₂ 1 CO₂Et 4-pyridyl 4-F-phenyl H H CH₂ 1 4-pyridylCO₂Et 4-F-phenyl H H CH₂ 1 CO₂H 4-pyridyl 4-F-phenyl H H CH₂ 1 CH₂OH4-pyridyl 4-F-phenyl H H CH₂ 1 CH₃ 4-pyridyl 4-F-phenyl H H CH₂ 1 H4-pyridyl 4-F-phenyl H H CH₂ 1 CO₂Et 4-pyridyl 2-thienyl- H H CH₂ 14-pyridyl CO₂Et 2-thienyl- H H CH₂ 1 CO₂H 4-pyridyl 2-thienyl- H H CH₂ 1H 4-pyridyl 2-thienyl- H H CH₂ 1 CO₂Et 4-pyridyl 5-Cl-2-thienyl- H H CH₂1 4-pyridyl CO₂Et 5-Cl-2-thienyl- H H S 1 CO₂Et 4-pyridyl 4-F-phenyl H HS 1 4-pyridyl CO₂Et 4-F-phenyl H H S 1 CO₂H 4-pyridyl 4-F-phenyl H H S 1CH₂OH 4-pyridyl 4-F-phenyl H H S 1 CH3 4-pyridyl 4-F-phenyl H H S 1 H4-pyridyl 4-F-phenyl H H CH₂ 2 CO₂Et 4-pyridyl 4-F-phenyl H H CH₂ 24-pyridyl CO₂Et 4-F-phenyl H H CH₂ 2 CH₂OH 4-pyridyl 4-F-phenyl H H CH₂2 CH₃ 4-pyridyl 4-F-phenyl H H CH₂ 2 H 4-pyridyl 4-F-phenyl H H CH₂ 1CO₂Et 4-F-phenyl 4-pyridyl H H CH₂ 1 4-F-phenyl CO₂Et 4-pyridyl H H CH₂1 CH₂OH 4-F-phenyl 4-pyridyl H H CH₂ 1 CH₃ 4-F-phenyl 4-pyridyl H H CH₂1 H 4-F-phenyl 4-pyridyl H H S 2 4-pyridyl 4-F-phenyl H CH₃ CH₃ O 24-pyridyl 4-F-phenyl H CH₃ CH₃ CH₂ 1 phenyl 4-F-phenyl 4-pyridyl H H CH₂1 phenyl 2,4-pyrimidyl CH₃ H H CH₂ 1 4-F-phenyl 2,4-pyrimidyl CH₃ H HCH₂ 1 CH₃ 4-F-phenyl 2,4-pyrimidyl H H CH₂ 1 phenyl 3-amino-2,4- CH₃ H Hpyrimidyl CH₂ 1 4-F-phenyl 3-amino-2,4- CH₃ H H pyrimidyl CH₂ 1 CH₃4-F-phenyl 3- amino-2,4- H H pyrimidyl


6. A pharmaceutical composition comprising at least one compound asclaimed in one of claims 1 to 5, if appropriate together withpharmaceutically acceptable vehicles and/or additives.
 7. The use of atleast one compound as claimed in one of claims 1 to 5 for thepreparation of a pharmaceutical composition for treating disorders whichare connected with a disturbance of the immune system.
 8. A procedurefor the treatment of disorders which are connected with a disturbance ofthe immune system, where an amount of a compound of the formula I asclaimed in claim 1 having immunomodulating action and/or inhibitingcytokine release is administered to a person who is in need of atreatment of this type.